Bicyclic compounds as inhibitors of diacyglycerol acyltransferase

ABSTRACT

The present invention relates to novel heterocyclic compounds as diacylglycerol acyltransferase (“DGAT”) inhibitors, pharmaceutical compositions comprising the heterocyclic compounds and the use of the compounds for treating or preventing a cardiovascular disease, a metabolic disorder, obesity or an obesity-related disorder, diabetes, dyslipidemia, a diabetic complication, impaired glucose tolerance or impaired fasting glucose. An illustrative compound of the invention is shown below (I).

FIELD OF THE INVENTION

The present invention relates to certain heterocyclic compounds usefulas diacylglycerol acyltransferase (“DGAT”) inhibitors, especiallydiacylglycerol acyltransferase 1 (“DGAT1”) inhibitors, pharmaceuticalcompositions containing the compounds, and methods of treatment usingthe compounds and compositions to treat or prevent various diseasesincluding cardiovascular disease, dyslipidemia, obesity and diabetes(e.g., Type 2 diabetes).

BACKGROUND OF THE INVENTION

There is a need for additional ways of treating diseases associated withmetabolic syndrome such as, for example, dyslipidemia, cardiovasculardisease, obesity and diabetes (e.g., Type 2 diabetes).

Triglycerides or triacylglycerols are the major form of energy storagein eukaryotic organisms. In mammals, these compounds are primarilysynthesized in three tissues: the small intestine, liver, andadipocytes. Triglycerides or triacylglycerols support the majorfunctions of dietary fat absorption, packaging of newly synthesizedfatty acids and storage in fat tissue (see Subauste and Burant, CurrentDrug Targets-Immune, Endocrine & Metabolic Disorders (2003) 3, pp.263-270).

Diacylglycerol O-acyltransferase, also known as diglycerideacyltransferase or DGAT, is a key enzyme in triglyceride synthesis. DGATcatalyzes the final and rate-limiting step in the triacylglycerolsynthesis from 1,2-diacylglycerol (DAG) and long chain fatty acyl CoA assubstrates. Thus, DGAT plays an essential role in the metabolism ofcellular diacylglycerol and is critically important for triglycerideproduction and energy storage homeostasis (see Mayorek et al, EuropeanJournal of Biochemistry (1989) 182, pp. 395-400).

Two forms of DGAT have been cloned and are designated DGAT1 and DGAT2[see Cases et al, Proceedings of the National Academy of Science, USA(1998) 95, pp. 13018-13023, Lardizabal et al, Journal of BiologicalChemistry (2001) 276, pp. 38862-38869 and Cases et al, Journal ofBiological Chemistry (2001) 276, pp. 38870-38876]. Although both enzymesutilize the same substrates, there is no homology between DGAT1 andDGAT2. Both enzymes are widely expressed. However, some differences doexist in the relative abundance of expression in various tissues.

Disorders or imbalances in triglyceride metabolism, both absorption aswell as de novo synthesis, have been implicated in the pathogenesis of avariety of disease risks. These include obesity, insulin resistancesyndrome, Type II diabetes, dyslipidemia, metabolic syndrome (syndromeX) and coronary heart disease [see Kahn, Nature Genetics (2000) 25, pp.6-7, Yanovski and Yanovski, New England Journal of Medicine (2002) 346,pp. 591-602, Lewis et al, Endocrine Reviews (2002) 23, pp. 201, Brazil,Nature Reviews Drug Discovery (2002) 1, pp. 408, Malloy and Kane,Advances in Internal Medicine (2001) 47, pp. 111, Subauste and Burant,Current Drug Targets-Immune, Endocrine & Metabolic Disorders (2003) 3,pp. 263-270 and Yu and Ginsberg, Annals of Medicine (2004) 36, pp.252-261]. Compounds that can decrease the synthesis of triglyceridesfrom diacylglycerol by inhibiting or lowering the activity of the DGATenzyme would be of value as therapeutic agents for the treatment ofdiseases associated with abnormal metabolism of triglycerides.

Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack etal, EP1219716 and Burrows et al, 26th National Medicinal ChemistrySymposium (1998) poster C-22), substituted amino-pyrimidino-oxazines(see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabataet al, Phytochemistry (1997) 46, pp. 683-687 and Casaschi et al, Journalof Nutrition (2004) 134, pp. 1340-1346), substituted benzyl-phosphonates(see Kurogi et al, Journal of Medicinal Chemistry (1996) 39, pp.1433-1437, Goto et al, Chemistry and Pharmaceutical Bulletin (1996) 44,pp. 547-551, Ikeda et al, Thirteenth International Symposium onAtherosclerosis (2003), abstract 2P-0401, and Miyata et al, JP2004067635), aryl alkyl acid derivatives (see Smith et al, WO2004100881and US20040224997), furan and thiophene derivatives (see WO2004022551),pyrrolo[1,2b]pyridazine derivatives (see Fox et al, WO2005103907), andsubstituted sulfonamides (see Budd Haeberlein and Buckett,WO20050442500).

Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (seeColman et al, Biochimica et Biophysica Acta (1992) pp. 1125, 203-9),2-bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of BiologicalChemistry (1985) 260, pp. 6528-6532), roselipins (see Noriko et al,(Journal of Antibiotics (1999) 52, pp. 815-826), amidepsin (see Tomodaet al, Journal of Antibiotics (1995) 48, pp. 42-7), isochromophilone,prenylflavonoids (see Chung et al, Planta Medica (2004) 70, v58-260),polyacetylenes (see Lee et al, Planta Medica (2004) 70, pp. 97-200),cochlioquinones (see Lee et al, Journal of Antibiotics (2003) 56, pp.967-969), tanshinones (see Ko et al, Archives of Pharmaceutical Research(2002) 25, pp. 446-448), gemfibrozil (see Zhu et al, Atherosclerosis(2002) 164, pp. 221-228), and substituted quinolones (see Ko et al,Planta Medica (2002) 68, pp. 1131-1133). Also known to be modulators ofDGAT activity are antisense oligonucleotides (see Monia and Graham,US20040185559).

DGAT inhibitors have been described. See, for example, PCT publicationUS 2007/0244096 (published Oct. 31, 2007; applicant: Japan Tobacco).Claim 1 therein discloses compounds of the formula:

wherein R³, R⁴, R⁵, R⁶, R⁷, X, Y, Z, L¹, L², W¹, W² and m are described.

See also WO 2007/126957 (published Nov. 8, 2007; applicant: NovartisPharma). Claim 1 therein discloses compounds of the formula:

A-L1-B—C-D-L2-E

wherein A, L1, B, C, D, L2 and E are described.

See also WO 2008/067257 (published Jun. 5, 2008; applicant: AbbottLaboratories). Claim 1 therein discloses compounds of the formula:

wherein A, Q, X, R^(x), R^(y), R^(za), R^(zb), r and s are described.

See also WO 2009/011285 (published Jan. 22, 2009; applicant: TaishoPharmaceutical Co.). Claim 1 therein discloses compounds of the formula:

Wherein are A, X, Y, Q, R¹, R^(2a), and R^(2b) are described.

Commonly owned U.S. provisional patent applications, Ser. Nos.61/115,991, 61/115,995, 61/116,000, 61/115,982, 61/115,985 and61/115,987, all filed Nov. 19, 2008, also describe DGAT inhibitors.

A need exists in the art, however, for additional DGAT inhibitors thathave efficacy for the treatment of metabolic disorders such as, forexample, obesity, Type II diabetes mellitus and metabolic syndrome.

SUMMARY OF THE INVENTION

In an embodiment, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, or pharmaceutically acceptable salts, solvates or esters ofsaid prodrug, the compound being represented by the Formula IA:

or a stereoisomer or tautomer of said compound, wherein

-   the bond denoted by    represents a single bond or a double bond;-   W is selected from the group consisting of C(R⁴), C(R⁴R⁴), N, N(R⁴),    S or O;-   X is selected from the group consisting of C(R⁴), C(R⁴R⁴), N, N(R⁴),    S or O;-   Y is selected from the group consisting of C(R⁴), C(R⁴R⁴), N, N(R⁴),    S or O;-   R⁴ is present depending on the allowed valency and R⁴ is selected    from H, alkyl, R¹, —OH, (═O), or hydroxyalkyl;-   W, X or Y is substituted with R¹ depending on the allowed valency;-   R¹ is selected from the group consisting of -alkyl, -aryl,    arylalkyl-, heteroaryl-, (heteroaryl)alkyl-, cycloalkyl-,    (cycloalkyl)alkyl-, heterocycloalkyl-, (heterocycloalkyl)alkyl-,    (alkyl)amino-, (aryl)amino-, (arylalkyl)amino-, (heteroaryl)amino-,    (heteroarylalkyl)amino-, (cycloalkyl)amino-,    ((cycloalkyl)alkyl)amino-, (heterocycloalkyl)amino-,    ((heterocycloalkyl)alkyl)amino-, (alkyl)carbonyl-,    (cycloalkyl)carbonyl-, ((cycloalkyl)alkyl)carbonyl-,    (heterocycloalkyl)carbonyl-, ((heterocyclyl)alkyl)carbonyl-,    (aryl)carbonyl-, ((aryl)alkyl)carbonyl-, (heteroaryl)carbonyl-,    ((heteroaryl)alkyl)carbonyl-, (alkyl)thiocarbonyl-,    (cycloalkyl)thiocarbonyl-, ((cycloalkyl)alkyl)thiocarbonyl-,    (heterocycloalkyl)thiocarbonyl-, ((heterocyclyl)alkyl)thiocarbonyl-,    (aryl)thiocarbonyl-, ((aryl)alkyl)thiocarbonyl-,    (heteroaryl)thiocarbonyl-, ((heteroaryl)alkyl)thiocarbonyl-,    (alkyloxy)carbonyl-, (cycloalkyloxy)carbonyl-,    (heterocycloalkyloxy)carbonyl-, (aryloxy)carbonyl-,    (arylalkyloxy)carbonyl-, (heteroaryloxy)carbonyl-,    (heteroarylalkyloxy)carbonyl-, (alkylamino)carbonyl-,    (cycloalkylamino)carbonyl-, (heterocycloalkylamino)carbonyl-,    (arylamino)carbonyl-, (arylalkylamino)carbonyl-;    (heteroarylamino)carbonyl-, (heteroarylalkylamino)carbonyl-,    (alkyl)sulfonyl-, (cycloalkyl)sulfonyl-,    (heterocycloalkyl)sulfonyl-, (aryl)sulfonyl-, (arylalkyl)sulfonyl-,    (heteroaryl)sulfonyl-, (heteroarylalkyl)sulfonyl-,    (alkylamino)sulfonyl-, (cycloalkylamino)sulfonyl-,    (heterocycloalkylamino)sulfonyl-, (arylamino)sulfonyl-,    (arylalkylamino)sulfonyl-, (heteroarylamino)sulfonyl- and    (heteroarylalkylamino)sulfonyl-, wherein each of these R¹ groups is    unsubstituted or optionally independently substituted with 1-4    substituents independently selected from halogen, amino, alkylamino,    hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester,    methylenedioxy, CN, cyanoalkyl-, nitro and CF₃;-   A is selected from the group consisting of C(R⁵) or N;-   B is selected from the group consisting of C(R⁵) or N;-   C is selected from the group consisting of C(R⁵) or N;-   D is selected from the group consisting of C(R⁵) or N;-   R⁵ is selected from H, alkyl, cycloalkyl, amino, alkylamino,    hydroxy, alkoxy, halogen or R²;-   A, B, C or D is optionally substituted, depending on the allowed    vacancy, with cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein    each of these groups is unsubstituted or optionally independently    substituted with 1-4 substituents independently selected from    halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN    and CF₃;-   R² is selected from the group consisting of cycloalkyl,    heterocyclyl, and aryl, wherein each of these R² groups is    unsubstituted or optionally independently substituted with 1-4    substituents independently selected from halogen, amino, alkylamino,    hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF₃;-   Z is selected from the group consisting of a bond, O, NR⁶, alkyl,    carbonyl and sulfonyl;-   R⁶ is selected from H or alkyl;-   R³ is selected from the group consisting of cycloalkyl,    heterocyclyl, aryl and heteroaryl, wherein each of these R³ groups    is unsubstituted or optionally independently substituted with 1-4    substituents independently selected from halogen, amino, alkylamino,    hydroxy, alkoxy, alkyl, cycloalkyl, —CN, —CF₃, —C(O)NH(R⁶),    —CON(R⁶)₂, —COOH, —C(O)—Oalkyl, -alkylCOOH, -alkyl-C(O)O-alkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)—NH—(CH₂)₁₋₃—CN,    -alkyl-C(O)—NH—(CH₂)₁₋₃-(heteroaryl), —COOH bioisostere or    -alkylCOOH bioisostere.

The term “COOH bioisostere” is as defined in The Practice of MedicinalChemistry, C. G. Wermuth Ed.; Academic Press: New York, 1996, p. 203.Non-limiting examples of COOH bioisosteres include —SO₃H, —S(O)₂NHR⁷,—S(O)₂NHC(O)R⁷, —CH₂S(O)₂R⁷, —C(O)NHS(O)₂R⁷, —C(O)NHOH, —C(O)NHCN,—CH(CF₃)OH, —C(CF₃)₂OH, —P(O)(OH)₂ and the groups listed below:

where R⁷ is selected from alkyl, aryl or heteroaryl.

In another aspect, this invention discloses a compound, orpharmaceutically acceptable salts, solvates, esters or prodrugs of saidcompound, or pharmaceutically acceptable salts, solvates or esters ofsaid prodrug, the compound being represented by the Formula IB:

or a stereoisomer or tautomer of said compound, wherein

-   the bond denoted by    represents a single bond or a double bond;-   E is selected from the group consisting of C(R⁴), C(R⁴R⁴), N, N→O,    N(R⁴), S or O;-   F is selected from the group consisting of C(R⁴), C(R⁴R⁴), N, N→O,    or NR⁴;-   G is selected from the group consisting of C(R⁴), C(R⁴R⁴), N, N→O or    NR⁴;-   H is selected from the group consisting of C(R⁴), C(R⁴R⁴), N, N→O,    N(R⁴), S or O;-   R⁴ is present depending on the allowed vacancy and is selected from    H, alkyl, R¹, —OH, (═O), or hydroxyalkyl;-   E, F, G or H is substituted with R¹ depending on the allowed    valency;-   R¹ is selected from the group consisting of alkyl-, aryl-,    arylalkyl-, heteroaryl-, (heteroaryl)alkyl-, cycloalkyl-,    (cycloalkyl)alkyl-, heterocycloalkyl-, (heterocycloalkyl)alkyl-,    (alkyl)amino-, (aryl)amino-, (arylalkyl)amino-, (heteroaryl)amino-,    (heteroarylalkyl)amino-, (cycloalkyl)amino-,    ((cycloalkyl)alkyl)amino-, (heterocycloalkyl)amino-,    ((heterocycloalkyl)alkyl)amino-, (alkyl)carbonyl-,    (cycloalkyl)carbonyl-, ((cycloalkyl)alkyl)carbonyl-,    (heterocycloalkyl)carbonyl-, ((heterocyclyl)alkyl)carbonyl-,    (aryl)carbonyl-, ((aryl)alkyl)carbonyl-, (heteroaryl)carbonyl-,    ((heteroaryl)alkyl)carbonyl-, (alkyl)thiocarbonyl-,    (cycloalkyl)thiocarbonyl-, ((cycloalkyl)alkyl)thiocarbonyl-,    (heterocycloalkyl)thiocarbonyl-, ((heterocyclyl)alkyl)thiocarbonyl-,    (aryl)thiocarbonyl-, ((aryl)alkyl)thiocarbonyl-,    (heteroaryl)thiocarbonyl-, ((heteroaryl)alkyl)thiocarbonyl-,    (alkyloxy)carbonyl-, (cycloalkyloxy)carbonyl-,    (heterocycloalkyloxy)carbonyl-, (aryloxy)carbonyl-,    (arylalkyloxy)carbonyl-, (heteroaryloxy)carbonyl-,    (heteroarylalkyloxy)carbonyl-, (alkylamino)carbonyl-,    (cycloalkylamino)carbonyl-, (heterocycloalkylamino)carbonyl-,    (arylamino)carbonyl-, (arylalkylamino)carbonyl-,    (heteroarylamino)carbonyl-, (heteroarylalkylamino)carbonyl-,    (alkyl)sulfonyl-, (cycloalkyl)sulfonyl-,    (heterocycloalkyl)sulfonyl-, (aryl)sulfonyl-, (arylalkyl)sulfonyl-,    (heteroaryl)sulfonyl-, (heteroarylalkyl)sulfonyl-,    (alkylamino)sulfonyl-, (cycloalkylamino)sulfonyl-,    (heterocycloalkylamino)sulfonyl-, (arylamino)sulfonyl-,    (arylalkylamino)sulfonyl-, (heteroarylamino)sulfonyl- and    (heteroarylalkylamino)sulfonyl- wherein each of these R¹ groups is    unsubstituted or optionally independently substituted with 1-4    substituents independently selected from halogen, amino, alkylamino,    hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester,    methylenedioxy, CN, cyanoalkyl-, nitro and CF₃;-   A is selected from the group consisting of CR⁵ or N;-   B is selected from the group consisting of CR⁵ or N;-   C is selected from the group consisting of CR⁵ or N;-   D is selected from the group consisting of CR⁵ or N;-   R⁵ is selected from H, alkyl, cycloalkyl, amino, alkylamino,    hydroxy, alkoxy, halogen or R²;-   A, B, C or D is optionally substituted, depending on the allowed    valency, with cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein    each of these groups is unsubstituted or optionally independently    substituted with 1-4 substituents independently selected from    halogen, amino, alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, CN    and CF₃;-   R² is selected from the group consisting of cycloalkyl,    heterocycloalkyl, or aryl, wherein each of these R² groups is    unsubstituted or optionally independently substituted with 1-4    substituents independently selected from halogen, amino, alkylamino,    hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF₃;-   Z is selected from the group consisting of a bond, O, NR⁶, alkyl,    carbonyl and sulfonyl;-   R⁶ is selected from H or alkyl; and-   R³ is selected from the group consisting of cycloalkyl,    heterocyclyl, aryl and heteroaryl, wherein each of these R³ groups    is unsubstituted or optionally independently substituted with 1-4    substituents independently selected from halogen, amino, alkylamino,    hydroxy, alkoxy, alkyl, cycloalkyl, —CN, —CF₃, —C(O)NH(R⁶),    —CON(R⁶)₂, —COOH, —C(O)—Oalkyl, -alkylCOOH, -alkyl-C(O)O-alkyl,    -alkyl-C(O)NH₂, -alkyl-C(O)—NH—(CH₂)₁₋₃—CN,    -alkyl-C(O)—NH—(CH₂)₁₋₃-(heteroaryl), —COOH bioisostere or    -alkylCOOH bioisostere.

The term “COOH bioisostere” is as defined under Formula IA.

In another aspect, this invention provides compositions comprising atleast one compound of Formula IA or Formula IB.

In another aspect, this invention provides pharmaceutical compositionscomprising at least one compound of Formula IA or Formula IB and atleast one pharmaceutically acceptable carrier.

In another aspect, this invention provides a method of treating diabetesin a patient in need of such treatment using therapeutically effectiveamounts of at least one compound of Formula IA or Formula IB, or of acomposition comprising at least one compound of Formula IA or FormulaIB.

In another aspect, this invention provides a method of treating diabetesin a patient in need of such treatment, e.g., Type 2 diabetes, usingtherapeutically effective amounts of at least one compound of Formula IAor Formula IB, or of a composition comprising at least one compound ofFormula IA or Formula IB.

In another aspect, this invention provides a method of treatingmetabolic syndrome in a patient in need of such treatment, usingtherapeutically effective amounts of at least one compound of Formula IAor Formula IB, or of a composition comprising at least one compound ofFormula IA or Formula IB.

In another aspect, this invention provides a method of inhibiting DGATusing therapeutically effective amounts of at least one compound ofFormula IA or Formula IB, or of a composition comprising at least onecompound of Formula IA or Formula IB.

In another aspect, this invention provides a method of inhibiting DGAT1using therapeutically effective amounts of at least one compound ofFormula IA or Formula IB, or of a composition comprising at least onecompound of Formula IA or Formula IB.

DESCRIPTION OF THE INVENTION

In an embodiment, the present invention discloses compounds of FormulaIA or Formula IB, or pharmaceutically acceptable salts, solvates, estersor prodrugs thereof.

The following embodiments (stated as “another embodiment”) areindependent of one another; different such embodiments can beindependently selected and combined in various combinations. Suchcombinations should be considered as part of the invention. The thusdescribed embodiments are applicable independently to Formula IA andFormula IB as appropriate.

In another embodiment, W is C(R⁴).

In another embodiment, W is C(R⁴R⁴).

In another embodiment, W is N.

In another embodiment, W is N(R⁴).

In another embodiment, W is S.

In another embodiment, W is O.

In another embodiment, X is C(R⁴).

In another embodiment, X is C(R⁴R⁴).

In another embodiment, X is N.

In another embodiment, X is N(R⁴).

In another embodiment, X is S.

In another embodiment, X is O.

In another embodiment, Y is C(R⁴).

In another embodiment, Y is C(R⁴R⁴).

In another embodiment, Y is N.

In another embodiment, Y is N(R⁴).

In another embodiment, Y is S.

In another embodiment, Y is O.

In another embodiment, W═X═N.

In another embodiment, W═Y═N.

In another embodiment, X═Y═N.

In another embodiment,

represents a single bond.

In another embodiment,

represents a double bond.

In another embodiment in Formula IB, both

represent double bonds.

In another embodiment in Formula IB, both

represent single bonds.

In another embodiment in Formula IB, one

represents a double bond and the other

represents a single bond.

In another embodiment, R¹ is alkyl.

In another embodiment, R¹ is aryl.

In another embodiment, R¹ is arylalkyl.

In another embodiment, R¹ is cycloalkyl.

In another embodiment, R¹ is cycloalkylalkyl.

In another embodiment, R¹ is heterocyclyl.

In another embodiment, R¹ is heterocyclylalkyl.

In another embodiment, R¹ is heteroaryl.

In another embodiment, R¹ is heteroarylalkyl.

In another embodiment, R¹ is alkylcarbonyl.

In another embodiment, R¹ is arylcarbonyl.

In another embodiment, R¹ is cycloalkylcarbonyl.

In another embodiment, R¹ is (cycloalkyl)alkylcarbonyl.

In another embodiment, R¹ is heteroarylcarbonyl.

In another embodiment, R¹ is heterocyclylcarbonyl.

In another embodiment, R¹ is (heterocyclyl)alkylcarbonyl.

In another embodiment, R¹ is (aryl)alkylcarbonyl.

In another embodiment, R¹ is (heteroaryl)alkylcarbonyl.

In another embodiment, R¹ is (alkylthio)carbonyl-.

In another embodiment, R¹ is (alkoxy)carbonyl-.

In another embodiment, R¹ is (alkylamino)carbonyl.

In another embodiment, R¹ is (arylamino)carbonyl-.

In another embodiment, R¹ is (heteroarylamino)carbonyl-.

In another embodiment, R¹ is (heterocyclylamino)carbonyl.

In another embodiment, R¹ is (cycloalkylamino)carbonyl.

In another embodiment, R¹ is (heterocyclylamino)sulfonyl.

In another embodiment, R¹ is (arylamino)sulfonyl-.

In another embodiment, R¹ is (heteroarylamino)sulfonyl.

In another embodiment, R¹ comes off a ring carbon on the ring shown inFormula IA or IB.

In another embodiment, R¹ comes off a ring nitrogen on the ring shown inFormula IA or IB.

In another embodiment, E is C(R⁴).

In another embodiment, E is C(R⁴R⁴).

In another embodiment, E is N.

In another embodiment, E is N(R⁴).

In another embodiment, E is S.

In another embodiment, E is O.

In another embodiment, H is C(R⁴).

In another embodiment, H is C(R⁴R⁴).

In another embodiment, H is N.

In another embodiment, H is N(R⁴).

In another embodiment, H is S.

In another embodiment, H is O.

In another embodiment, F is C(R⁴).

In another embodiment, F is C(R⁴R⁴).

In another embodiment, F is N.

In another embodiment, F is N(R⁴).

In another embodiment, G is C(R⁴).

In another embodiment, G is C(R⁴R⁴).

In another embodiment, G is N.

In another embodiment, G is N(R⁴).

In another embodiment, E=F═N.

In another embodiment, E=G=N.

In another embodiment, F═H═N.

In another embodiment, E=F=G=H.

In another embodiment, A is C(R⁵).

In another embodiment, A is N.

In another embodiment, B is C(R⁵).

In another embodiment, B is N.

In another embodiment, C is C(R⁵).

In another embodiment, C is N.

In another embodiment, D is C(R⁵).

In another embodiment, D is N.

In another embodiment, R⁵ is H.

In another embodiment, R⁵ is alkyl.

In another embodiment, R⁵ is methyl.

In another embodiment, R⁵ is cycloalkyl.

In another embodiment, R⁵ is amino.

In another embodiment, R⁵ is alkylamino.

In another embodiment, R⁵ is —OH.

In another embodiment, R⁵ is alkoxy.

In another embodiment, R⁵ is halo.

In another embodiment, R⁵ is chloro.

In another embodiment, R⁵ is R², where R² is as defined.

In another embodiment, R² is cycloalkyl.

In another embodiment, R² is aryl.

In another embodiment, R² is heterocyclyl.

In another embodiment, R⁶ is H.

In another embodiment, R⁶ is alkyl.

In another embodiment, Z is a bond.

In another embodiment, Z is O.

In another embodiment, Z is N(R⁴).

In another embodiment, Z is alkyl.

In another embodiment, Z is carbonyl.

In another embodiment, Z is sulfonyl.

In another embodiment, R³ is cycloalkyl.

In another embodiment, R³ is aryl.

In another embodiment, R³ is heteroaryl.

In another embodiment, R³ is heterocyclyl.

In another embodiment, R³ is unsubstituted.

In another embodiment, R³ is substituted with one moiety as describedearlier.

In another embodiment, R³ is substituted with more than one moiety asdescribed earlier.

In another embodiment, R³ is substituted with an alkyl.

In another embodiment, R³ is substituted with a lower alkyl.

In another embodiment, R³ is substituted with a —C(O)NH(R⁶).

In another embodiment, R³ is substituted with a —C(O)N(R⁶)₂.

In another embodiment, R³ is substituted with a carboxyl orcarboxyester.

In another embodiment, R³ is substituted with COOH bioisostere, whereinCOOH bioisostere is as defined earlier.

In another embodiment, R³ is substituted with halo.

In another embodiment, R³ is substituted with cyano.

In another embodiment, R³ is substituted with —OR⁵.

In another embodiment, R³ is substituted with —N(R⁴R⁵).

In another embodiment, R³ is substituted with —C(O)—N(R⁴R⁵).

In another embodiment, R³ is substituted with both halo and carboxyl.

In another embodiment, R³ is substituted with both —OR⁵ and carboxyl.

In another embodiment, R³ is substituted with both carboxy and alkyl-.

In another embodiment, R³ is substituted with -alkyl)-C(O)N(R⁴R⁵).

In another embodiment, in Formula IA, the moiety:

represents the moiety:

In another embodiment, in Formula IA, the moiety:

represents the moiety:

In another embodiment, in Formula IA, the moiety:

represents the moiety:

In another embodiment, in Formula IA, the moiety:

represents the moiety:

In another embodiment, in Formula IA, the moiety:

represents the moiety:

In another embodiment, in Formula IB, the moiety:

represents the moiety:

In another embodiment, in Formula IB, the moiety:

represents the moiety:

In another embodiment, in Formula IB, the moiety:

represents the moiety:

In another embodiment, in Formula IB, the moiety:

represents the moiety:

In another embodiment, in Formula IB, the moiety:

represents the moiety:

In another embodiment, in Formula IB, the moiety:

represents the moiety:

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis C, X is C, Y is C, Z is aryl, and the others are as previouslydefined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is C, Y is C, Z is aryl, and the others are as previouslydefined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is aryl, and the others are as previouslydefined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is aryl, R¹ is (arylamino)carbonyl, and theothers are as previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is aryl, R¹ is (arylamino)carbonyl, and theothers are as previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is aryl, R¹ is arylcarbonyl, and the others areas previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is aryl, R¹ is arylcarbonyl, R³ is cycloalkyl,and the others are as previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is phenyl, R¹ is (arylamino)carbonyl, and theothers are as previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is phenyl, R¹ is (arylamino)carbonyl, R³ iscycloalkyl, and the others are as previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is biphenyl, R¹ is (arylamino)carbonyl, and theothers are as previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is biphenyl, R¹ is (arylamino)carbonyl, R³ iscycloalkyl, and the others are as previously defined.

In another embodiment of Formula IA or Formula IB, wherein X, Y, W, Z,R¹, R², and R³ and any remaining moieties are independently selected, Wis N, X is N, Y is C, Z is biphenyl, R¹ is (arylamino)carbonyl, R³ iscycloalkyl, and the others are as previously defined.

Non-limiting examples of the compounds of Formula IA or Formula IB areshown below as well as in the Examples section:

or pharmaceutically acceptable salts, solvates, esters and prodrugsthereof.

Additional non-limiting examples of the present invention are thecompounds of the following formula:

or pharmaceutically acceptable salts, solvates, esters and prodrugsthereof.

Several of the above-noted compounds exhibited IC50 values less than 3μM in the assay described on page 84. Many compounds exhibited IC50values less than 1 μM, with some compounds under <100 nM.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both humans and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.Lower alkyl means a group having about 1 to about 6 carbon atoms in thechain which may be straight or branched. Alkyl may be unsubstituted oroptionally substituted by one or more substituents which may be the sameor different, each substituent being independently selected from thegroup consisting of halo, alkyl, aryl, cycloalkyl, cyano, pyridine,alkoxy, alkylthio, amino, oxime (e.g., ═N—OH), —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, carboxy and —C(O)O-alkyl. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl andt-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. Lower alkenyl meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Alkenyl may be unsubstituted or optionally substituted by oneor more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. Lower alkynyl meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. Alkynyl may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridine (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” or “halo” means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro,cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl,—C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl), oxime (e.g., ═N—OH),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso mean a single moiety (e.g., carbonyl) which simultaneously replacestwo available hydrogens on the same carbon atom on a ring system.Example of such moiety is pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in heteroatom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Alkoxyalkyl-” means an alkyl-O-alkyl- group in which the alkyl group isas previously described. Non-limiting examples of suitable alkoxyalkylgroups include methoxymethyl, ethoxymethyl, n-propoxyethyl,isopropoxyethyl and n-butoxymethyl. The bond to the parent moiety isthrough the alkyl.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aryloxyalkyl-” means an aryl-O-alkyl- group in which the aryl and arylgroups are as previously described. Non-limiting examples of suitablearyloxyalkyl groups include phenoxymethyl and naphthoxyethyl. The bondto the parent moiety is through the alkyl.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Alkylthioalkyl-” means an alkyl-S-alkyl- group in which the alkyl groupis as previously described. Non-limiting examples of suitablealkylthioalkyl groups include methylthioethyl and ethylthiomethyl. Thebond to the parent moiety is through the alkyl.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthioalkyl-” means an aryl-S-alkyl- group in which the aryl group isas previously described. Non-limiting examples of suitable arylthioalkylgroups include phenylthioethyl and phenylthiomethyl. The bond to theparent moiety is through the alkyl.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula IA or Formula IB, itsdefinition on each occurrence is independent of its definition at everyother occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula IAor Formula IB or a pharmaceutically acceptable salt, hydrate or solvateof the compound. The transformation may occur by various mechanisms(e.g., by metabolic or chemical processes), such as, for example,through hydrolysis in blood. A discussion of the use of prodrugs isprovided by T. Higuchi and W. Stella, “Pro-drugs as Novel DeliverySystems,” Vol. 14 of the A.C.S. Symposium Series, and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987.

For example, if a compound of Formula IA or Formula IB or apharmaceutically acceptable salt, hydrate or solvate of the compoundcontains a carboxylic acid functional group, a prodrug can comprise anester formed by the replacement of the hydrogen atom of the acid groupwith a group such as, for example, (C₁-C₈)alkyl,(C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbonatoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula IA or Formula IB contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula IA or Formula IB incorporates an aminefunctional group, a prodrug can be formed by the replacement of ahydrogen atom in the amine group with a group such as, for example,R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl isa natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl andY³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., (2004) 93 (3), pp. 601-611describe the preparation of the solvates of the antifungal fluconazolein ethyl acetate as well as from water. Similar preparations ofsolvates, hemisolvate, hydrates and the like are described by E. C. vanTonder et al, AAPS PharmSciTech., (2004) 5 (1), article 12; and A. L.Bingham et al, Chem. Commun., (2001) pp. 603-604. A typical,non-limiting, process involves dissolving the inventive compound indesired amounts of the desired solvent (organic or water or mixturesthereof) at a higher than ambient temperature, and cooling the solutionat a rate sufficient to form crystals which are then isolated bystandard methods. Analytical techniques such as, for example I. R.spectroscopy, show the presence of the solvent (or water) in thecrystals as a solvate (or hydrate).

The term “effective” or ‘therapeutically effective” is used herein,unless otherwise indicated, to describe an amount of a compound orcomposition which, in context, is used to produce or effect an intendedresult or therapeutic effect as understood in the common knowledge ofthose skilled in the art.

The compounds of Formula IA or Formula IB can form salts which are alsowithin the scope of this invention. Reference to a compound of FormulaIA or Formula IB herein is understood to include reference to saltsthereof, unless otherwise indicated. The term “salt(s)”, as employedherein, denotes acidic salts formed with inorganic and/or organic acids,as well as basic salts formed with inorganic and/or organic bases. Inaddition, when a compound of Formula IA or Formula IB contains both abasic moiety, such as, but not limited to a pyridine or imidazole, andan acidic moiety, such as, but not limited to a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm “salt(s)” as used herein. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful. Salts of the compounds of the Formula IA orFormula IB may be formed, for example, by reacting a compound of FormulaIA or Formula IB with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) pp. 1-19; P. Gould, International J. of Pharmaceutics (1986) (2001)33, pp. 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the groups, in which the non-carbonyl moiety of the carboxylic acidportion of the ester grouping is selected from straight or branchedchain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl),alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl),aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyloptionally substituted with, for example, halogen, C₁₋₄alkyl, orC₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl- oraralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

Compounds of Formula IA or Formula IB, and salts, solvates, esters andprodrugs thereof, may exist in their tautomeric form (for example, as anamide or imino ether). All such tautomeric forms are contemplated hereinas part of the present invention.

The compounds of Formula IA or Formula IB may contain asymmetric orchiral centers, and, therefore, exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of FormulaIA or Formula IB as well as mixtures thereof, including racemicmixtures, form part of the present invention. In addition, the presentinvention embraces all geometric and positional isomers. For example, ifa compound of Formula IA or Formula IB incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula IA or Formula IB may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of chiral HPLCcolumn.

It is also possible that the compounds of Formula IA or Formula IB mayexist in different tautomeric forms, and all such forms are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula IA or Formula IB incorporates a double bond ora fused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention.) Individual stereoisomers of the compounds of the inventionmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I,respectively.

Certain isotopically-labelled compounds of Formula IA or Formula IB(e.g., those labeled with ³H and ¹⁴C) are useful in compound and/orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴O) isotopes are particularly preferred for their ease ofpreparation and detectability. Certain isotopically-labelled compoundsof Formula IA or Formula IB can be useful for medical imaging purposes.e.g., those labeled with positron-emitting isotopes like ¹¹C or ¹⁸F canbe useful for application in Positron Emission Tomography (PET) andthose labeled with gamma ray emitting isotopes like ¹²³I can be usefulfor application in Single Photon Emission Computed Tomography (SPECT).Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence may be preferred in some circumstances. Further,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence may be preferred in some circumstances.Additionally, isotopic substitution at a site where epimerization occursmay slow or reduce the epimerization process and thereby retain the moreactive or efficacious form of the compound for a longer period of time.Isotopically labeled compounds of Formula IA or Formula IB, inparticular those containing isotopes with longer half lives (T1/2>1day), can generally be prepared by following procedures analogous tothose disclosed in the Schemes and/or in the Examples herein below, bysubstituting an appropriate isotopically labeled reagent for anon-isotopically labeled reagent.

Polymorphic forms of the compounds of Formula IA or Formula IB, and ofthe salts, solvates, esters and prodrugs of the compounds of Formula IAor Formula IB, are intended to be included in the present invention.

The compounds according to the invention have pharmacologicalproperties. The compounds of Formula IA or Formula IB are inhibitors ofDGAT, particularly DGAT1, and can be useful for the therapeutic and/orprophylactic treatment of diseases that are modulated by DGAT,particularly by DGAT1, such as, for example, metabolic syndrome,diabetes (e.g., Type 2 diabetes mellitus), obesity and the like.

The invention also includes methods of treating diseases that aremodulated by DGAT, particularly by DGAT1.

The invention also includes methods of treating metabolic syndrome,diabetes (e.g., Type 2 diabetes mellitus), and obesity in a patient byadministering at least one compound of Formula IA or Formula IB to saidpatient.

Diabetes refers to a disease process derived from multiple causativefactors and is characterized by elevated levels of plasma glucose, orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Abnormal glucose homeostasis is associated with alterationsof the lipid, lipoprotein and apolipoprotein metabolism and othermetabolic and hemodynamic disease. As such, the diabetic patient is atespecially increased risk of macrovascular and microvascularcomplications, including coronary heart disease, stroke, peripheralvascular disease, hypertension, nephropathy, neuropathy, andretinopathy. Accordingly, therapeutic control of glucose homeostasis,lipid metabolism and hypertension are critically important in theclinical management and treatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In Type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissue(muscle, liver and adipose tissue), and the plasma insulin levels, whileelevated, are insufficient to overcome the pronounced insulinresistance.

Insulin resistance is not associated with a diminished number of insulinreceptors but rather to a post-insulin receptor binding defect that isnot well understood. This resistance to insulin responsiveness resultsin insufficient insulin activation of glucose uptake, oxidation andstorage in muscle, and inadequate insulin repression of lipolysis inadipose tissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic [beta]-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides are a class of agents that can increaseinsulin sensitivity and bring about some degree of correction ofhyperglycemia. However, the biguanides can induce lactic acidosis andnausea/diarrhea.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a separateclass of compounds with potential for the treatment of Type 2 diabetes.These agents increase insulin sensitivity in muscle, liver and adiposetissue in several animal models of Type 2 diabetes, resulting in partialor complete correction of the elevated plasma levels of glucose withoutoccurrence of hypoglycemia. The glitazones that are currently marketedare agonists of the peroxisome proliferator activated receptor (PPAR),primarily the PPAR-gamma subtype. PPAR-gamma agonism is generallybelieved to be responsible for the improved insulin sensititization thatis observed with the glitazones. Newer PPAR agonists that are beingtested for treatment of Type 2 diabetes are agonists of the alpha, gammaor delta subtype, or a combination of these, and in many cases arechemically different from the glitazones (i.e., they are notthiazolidinediones). Serious side effects (e.g. liver toxicity) havebeen noted in some patients treated with glitazone drugs, such astroglitazone.

Additional methods of treating the disease are currently underinvestigation. New biochemical approaches include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (DPP-IV)enzyme are also under investigation as drugs that may be useful in thetreatment of diabetes, and particularly Type 2 diabetes.

The invention includes compositions, e.g., pharmaceutical compositions,comprising at least one compound of Formula IA or Formula IB. Forpreparing pharmaceutical compositions from the compounds described bythis invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Other carriers include Poloxamer,Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol,polyethylene glycol (PEG) 400, propylene glycol, Trappsol,alpha-cyclodextrin or analogs thereof, beta-cyclodextrin or analogsthereof, or gamma-cyclodextrin or analogs thereof. Examples ofpharmaceutically acceptable carriers and methods of manufacture forvarious compositions may be found in A. Gennaro (ed.), Remington'sPharmaceutical Sciences, 18^(th) Edition, (1990), Mack Publishing Co.,Easton, Pa.

The therapeutic agents of the present invention are preferablyformulated in pharmaceutical compositions and then, in accordance withthe methods of the invention, administered to a subject, such as a humansubject, in a variety of forms adapted to the chosen route ofadministration. For example, the therapeutic agents may be formulatedfor intravenous administration. The formulations may, however, includethose suitable for oral, rectal, vaginal, topical, nasal, ophthalmic, orother parenteral administration (including subcutaneous, intramuscular,intrathecal, intraperitoneal and intratumoral, in addition tointravenous) administration.

Formulations suitable for parenteral administration conveniently includea sterile aqueous preparation of the active agent, or dispersions ofsterile powders of the active agent, which are preferably isotonic withthe blood of the recipient. Parenteral administration of the therapeuticagents (e.g., through an I.V. drip) is an additional form ofadministration. Isotonic agents that can be included in the liquidpreparation include sugars, buffers, and sodium chloride. Solutions ofthe active agents can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions of the active agent can be prepared inwater, ethanol, a polyol (such as glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, glycerol esters,and mixtures thereof. The ultimate dosage form is sterile, fluid, andstable under the conditions of manufacture and storage. The necessaryfluidity can be achieved, for example, by using liposomes, by employingthe appropriate particle size in the case of dispersions, or by usingsurfactants. Sterilization of a liquid preparation can be achieved byany convenient method that preserves the bioactivity of the activeagent, preferably by filter sterilization. Preferred methods forpreparing powders include vacuum drying and freeze drying of the sterileinjectible solutions. Subsequent microbial contamination can beprevented using various antimicrobial agents, for example,antibacterial, antiviral and antifungal agents including parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Absorptionof the active agents over a prolonged period can be achieved byincluding agents for delaying, for example, aluminum monostearate andgelatin.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as tablets, troches, capsules,lozenges, wafers, or cachets, each containing a predetermined amount ofthe active agent as a powder or granules, as liposomes containing thefirst and/or second therapeutic agents, or as a solution or suspensionin an aqueous liquor or non-aqueous liquid such as a syrup, an elixir,an emulsion, or a draught. Such compositions and preparations maycontain at least about 0.1 wt-% of the active agent. The amounts of thetherapeutic agents should be such that the dosage level will beeffective to produce the desired result in the subject.

Nasal spray formulations include purified aqueous solutions of theactive agent with preservative agents and isotonic agents. Suchformulations are preferably adjusted to a pH and isotonic statecompatible with the nasal mucous membranes. Formulations for rectal orvaginal administration may be presented as a suppository with a suitablecarrier such as cocoa butter, or hydrogenated fats or hydrogenated fattycarboxylic acids. Ophthalmic formulations are prepared by a similarmethod to the nasal spray, except that the pH and isotonic factors arepreferably adjusted to match that of the eye. Topical formulationsinclude the active agent dissolved or suspended in one or more mediasuch as mineral oil, petroleum, polyhydroxy alcohols, or other basesused for topical pharmaceutical formulations.

The tablets, troches, pills, capsules, and the like may also contain oneor more of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acid,and the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, fructose, lactose, or aspartame; and a natural orartificial flavoring agent. When the unit dosage form is a capsule, itmay further contain a liquid carrier, such as a vegetable oil or apolyethylene glycol. Various other materials may be present as coatingsor to otherwise modify the physical form of the solid unit dosage form.For instance, tablets, pills, or capsules may be coated with gelatin,wax, shellac, sugar, and the like. A syrup or elixir may contain one ormore of a sweetening agent, a preservative such as methyl- orpropylparaben, an agent to retard crystallization of the sugar, an agentto increase the solubility of any other ingredient, such as a polyhydricalcohol, for example glycerol or sorbitol, a dye, and flavoring agent.The material used in preparing any unit dosage form is substantiallynontoxic in the amounts employed. The active agent may be incorporatedinto sustained-release preparations and devices.

Preferably the compound is administered orally, intraperitoneally, orintravenously or intrathecally or some suitable combination(s) thereof.

Methods of administering small molecule therapeutic agents arewell-known in the art.

The therapeutic agents described in the present disclosure can beadministered to a subject alone or together (coadministered, optionallybut not necessarily, in a single formulation) with other active agentsas described herein, and are preferably administered with apharmaceutically acceptable buffer. The therapeutic agents can becombined with a variety of physiological acceptable carriers, additivesfor delivery to a subject, including a variety of diluents or excipientsknown to those of ordinary skill in the art. For example, for parenteraladministration, isotonic saline is preferred. For topicaladministration, a cream, including a carrier such as dimethylsulfoxide(DMSO), or other agents typically found in topical creams that do notblock or inhibit activity of the peptide, can be used. Other suitablecarriers include, but are not limited to, alcohol, phosphate bufferedsaline, and other balanced salt solutions.

The formulations may be conveniently presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.Preferably, such methods include the step of bringing the therapeuticagent (i.e., the active agent) into association with a carrier thatconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive agent into association with a liquid carrier, a finely dividedsolid carrier, or both, and then, if necessary, shaping the product intothe desired formulations. The methods of the invention includeadministering the therapeutic agents to a subject in an amount effectiveto produce the desired effect. The therapeutic agents can beadministered as a single dose or in multiple doses. Useful dosages ofthe active agents can be determined by comparing their in vitro activityand the in vivo activity in animal models.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula IA or Formula IB,or a pharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound and a pharmaceutically acceptable carrier, vehicle or diluent.

Another aspect of the invention includes pharmaceutical compositionscomprising at least one compound of Formula IA or Formula IB and atleast one other therapeutic agent in combination. Non-limiting examplesof such combination agents are described below. The agents in thecombination can be administered together as a joint administration(e.g., joint single pill), separately, one after the other in any orderand the like as is well known in the art.

In the combination therapies of the present invention, an effectiveamount can refer to each individual agent or to the combination as awhole, wherein the amounts of all agents administered are togethereffective, but wherein the component agent of the combination may not bepresent individually in an effective amount.

Combination Therapy

Accordingly, in one embodiment, the present invention provides methodsfor treating a Condition in a patient, the method comprisingadministering to the patient one or more Compounds of Formula IA orFormula IB, or a pharmaceutically acceptable salt or solvate thereof andat least one additional therapeutic agent that is not a Compound ofFormula IA or Formula IB, wherein the amounts administered are togethereffective to treat or prevent a Condition.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts).

In one embodiment, the one or more Compounds of Formula IA or Formula IBis administered during a time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the one or more Compounds of Formula IA orFormula IB and the additional therapeutic agent(s) are administered indoses commonly employed when such agents are used as monotherapy fortreating a Condition.

In another embodiment, the one or more Compounds of Formula IA orFormula IB and the additional therapeutic agent(s) are administered indoses lower than the doses commonly employed when such agents are usedas monotherapy for treating a Condition.

In still another embodiment, the one or more Compounds of Formula IA orFormula IB and the additional therapeutic agent(s) act synergisticallyand are administered in doses lower than the doses commonly employedwhen such agents are used as monotherapy for treating a Condition.

In one embodiment, the one or more Compounds of Formula IA or Formula IBand the additional therapeutic agent(s) are present in the samecomposition. In one embodiment, this composition is suitable for oraladministration. In another embodiment, this composition is suitable forintravenous administration.

The one or more Compounds of Formula IA or Formula IB and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

In one embodiment, the administration of one or more Compounds ofFormula IA or Formula IB and the additional therapeutic agent(s) mayinhibit the resistance of a Condition to these agents.

In one embodiment, when the patient is treated for diabetes, a diabeticcomplication, impaired glucose tolerance or impaired fasting glucose,the other therapeutic is an antidiabetic agent which is not a Compoundof Formula IA or Formula IB.

In another embodiment, the other therapeutic agent is an agent usefulfor reducing any potential side effect of a Compound of Formula IA orFormula IB. Such potential side effects include, but are not limited to,nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea,general pain, and pain at an injection site.

In one embodiment, the other therapeutic agent is used at its knowntherapeutically effective dose. In another embodiment, the othertherapeutic agent is used at its normally prescribed dosage. In anotherembodiment, the other therapeutic agent is used at less than itsnormally prescribed dosage or its known therapeutically effective dose.

Examples of antidiabetic agents useful in the present methods fortreating diabetes or a diabetic complication include a sulfonylurea; aninsulin sensitizer (such as a PPAR agonist, a DPP-IV inhibitor, a PTP-1Binhibitor and a glucokinase activator); a glucosidase inhibitor; aninsulin secretagogue; a hepatic glucose output lowering agent; ananti-obesity agent; a meglitinide; an agent that slows or blocks thebreakdown of starches and sugars in vivo; an histamine H₃ receptorantagonist; a sodium glucose uptake transporter 2 (SGLT-2) inhibitor; apeptide that increases insulin production; and insulin or anyinsulin-containing composition.

In one embodiment, the antidiabetic agent is an insulin sensitizer or asulfonylurea.

Non-limiting examples of sulfonylureas include glipizide, tolbutamide,glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide,gliclazide, glibenclamide and tolazamide.

Non-limiting examples of insulin sensitizers include PPAR activators,such as rosiglitazone, pioglitazone and englitazone; biguanidines suchas metformin and phenformin; DPP-IV inhibitors; PTP-1B inhibitors; andα-glucokinase activators, such as miglitol, acarbose, and voglibose.

Non-limiting examples of DPP-IV inhibitors useful in the present methodsinclude sitagliptin (Januvia™, Merck), saxagliptin, denagliptin,vildagliptin (Galvus™, Novartis), alogliptin, alogliptin benzoate,ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph),BI-A and BI-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513(Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination ofsitagliptin/metformin HCl (Janumet™, Merck).

Non-limiting examples of SGLT-2 inhibitors useful in the present methodsinclude dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) andT-1095 (Tanabe Seiyaku).

Non-limiting examples of hepatic glucose output lowering agents includeGlucophage and Glucophage XR.

Non-limiting examples of histamine H₃ receptor antagonist agents includethe following compound:

Non-limiting examples of insulin secretagogues include sulfonylurea andnon-sulfonylurea drugs such as GLP-1, a GLP-1 mimetic, exendin, GIP,secretin, glipizide, chlorpropamide, nateglinide, meglitinide,glibenclamide, repaglinide and glimepiride.

Non-limiting examples of GLP-1 mimetics useful in the present methodsinclude Byetta-Exenatide, Liraglutide, CJC-1131 (ConjuChem,Exenatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (ZealandPharmaceuticals), and compounds disclosed in International PublicationNo. WO 00/07617.

The term “insulin” as used herein, includes all pyridinones of insulin,including long acting and short acting forms of insulin.

Non-limiting examples of orally administrable insulin and insulincontaining compositions include AL-401 from AutoImmune, and thecompositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405;4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632;6,191,105; and International Publication No. WO 85/05029, each of whichis incorporated herein by reference.

In one embodiment, the antidiabetic agent is an anti-obesity agent.

Non-limiting examples of anti-obesity agents useful in the presentmethods for treating diabetes include a 5-HT2C agonist, such aslorcaserin; a neuropeptide Y antagonist; an MCR4 agonist; an MCHreceptor antagonist; a protein hormone, such as leptin or adiponectin;an AMP kinase activator; and a lipase inhibitor, such as orlistat.Appetite suppressants are not considered to be within the scope of theanti-obesity agents useful in the present methods.

Non-limiting examples of meglitinides useful in the present methods fortreating diabetes include repaglinide and nateglinide.

Non-limiting examples of insulin sensitizing agents include biguanides,such as metformin, metformin hydrochloride (such as GLUCOPHAGE® fromBristol-Myers Squibb), metformin hydrochloride with glyburide (such asGLUCOVANCE™ from Bristol-Myers Squibb) and buformin; glitazones; andthiazolidinediones, such as rosiglitazone, rosiglitazone maleate(AVANDIA™ from GlaxoSmithKline), pioglitazone, pioglitazonehydrochloride (ACTOST™, from Takeda) ciglitazone and MCC-555 (MitsubishiChemical Co.)

In one embodiment, the insulin sensitizer is a thiazolidinedione.

In another embodiment, the insulin sensitizer is a biguanide.

In another embodiment, the insulin sensitizer is a DPP-IV inhibitor.

In a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.

Non-limiting examples of antidiabetic agents that slow or block thebreakdown of starches and sugars and are suitable for use in thecompositions and methods of the present invention includealpha-glucosidase inhibitors and certain peptides for increasing insulinproduction. Alpha-glucosidase inhibitors help the body to lower bloodsugar by delaying the digestion of ingested carbohydrates, therebyresulting in a smaller rise in blood glucose concentration followingmeals. Non-limiting examples of suitable alpha-glucosidase inhibitorsinclude acarbose; miglitol; camiglibose; certain polyamines as disclosedin WO 01/47528 (incorporated herein by reference); voglibose.Non-limiting examples of suitable peptides for increasing insulinproduction including amlintide (CAS Reg. No. 122384-88-7 from Amylin;pramlintide, exendin, certain compounds having Glucagon-like peptide-1(GLP-1) agonistic activity as disclosed in WO 00/07617 (incorporatedherein by reference).

Non-limiting examples of orally administrable insulin and insulincontaining compositions include AL-401 from AutoImmune, and thecompositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405;4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632;6,191,105; and International Publication No. WO 85/05029, each of whichis incorporated herein by reference.

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention of aCondition can be determined by the attending clinician, taking intoconsideration the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the patient; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the Compound(s) of Formula IA or Formula IBand the other agent(s) for treating diseases or conditions listed abovecan be administered simultaneously or sequentially. This is particularlyuseful when the components of the combination are given on differentdosing schedules, e.g., one component is administered once daily andanother every six hours, or when the preferred pharmaceuticalcompositions are different, e.g. one is a tablet and one is a capsule. Akit comprising the separate dosage forms is therefore advantageous.

Generally, a total daily dosage of the one or more Compounds of FormulaIA or Formula IB and the additional therapeutic agent(s) can, whenadministered as combination therapy, range from about 0.1 to about 2000mg per day, although variations will necessarily occur depending on thetarget of the therapy, the patient and the route of administration. Inone embodiment, the dosage is from about 0.2 to about 1000 mg/day,administered in a single dose or in 2-4 divided doses. In anotherembodiment, the dosage is from about 1 to about 500 mg/day, administeredin a single dose or in 2-4 divided doses. In another embodiment, thedosage is from about 1 to about 200 mg/day, administered in a singledose or in 2-4 divided doses. In still another embodiment, the dosage isfrom about 1 to about 100 mg/day, administered in a single dose or in2-4 divided doses. In yet another embodiment, the dosage is from about 1to about 50 mg/day, administered in a single dose or in 2-4 divideddoses. In a further embodiment, the dosage is from about 1 to about 20mg/day, administered in a single dose or in 2-4 divided doses.

The compounds of the invention can be made according to the processesdescribed below. The compounds of this invention are also exemplified inthe examples below, which examples should not be construed as limitingthe scope of the disclosure. Alternative mechanistic pathways andanalogous structures within the scope of the invention may be apparentto those skilled in the art.

General Methods of Synthesis

The general methods described in this paragraph were used unless statedotherwise in the experimental procedures below. All solvents andreagents were used as received. Alternatively, anhydrousN,N-dimethylformamide, methylene chloride and tetrahydrofuran wereobtained by drying bulk solvents purchased from Fisher Scientific onactivated columns using the Pure-Solv PS-MD 3 system from InovativeTechnology. Proton NMR spectra were obtained using a Varian XL-400 (400MHz) or a Bruker Avance (500 MHz) instruments. ¹H chemical shifts arereported in parts per million (ppm), measured relative to residualsolvent peaks as an internal standard set to δ 7.26 ppm forchloroform-d, 3.34 for methanol-d₄ and 2.50 ppm for DMSO-d₆. LCMSanalyses were performed using a PE SCIEX API-150EX single quadrupolemass spectrometer equipped with a Phenomenex Gemini C₁₈ column (5.0 μm,50×4.6 mm); mobile phase A: 0.05% trifluoroacetic acid in water, B:0.05% trifluoroacetic acid in acetonitrile; gradient: 90% A and 10% B to5% A and 95% B in 5 mins. Alternatively, LCMS analyses were performedusing an Agilent 6140 quadrupole mass spectrometer equipped with aZorbax SB-C-18 C₁₈ column (1.8 μm, 50×4.6 mm) heated at 50° C.; mobilephase A: 0.1% trifluoroacetic acid in water, B: 0.1% trifluoroaceticacid in acetonitrile; gradient: 90% A and 10% B to 5% A and 95% B in 3.5mins. Flash column chromatography was performed using Teledyne IscoRediSep silica columns and C₁₈ reverse phase columns. Preparative HPLCseparations were performed on Gilson instruments (system 1: Gilson 322pump, UV-vis detector 156, liquid handler 215 and injector 845Z; orsystem 2: pumps 333 & 334, liquid handler GX281, UV-vis detector 155)using Phenomenex columns (Gemini C₁₈ 5.0 μm, 100×21.2 mm or 150×21.2 mmor 150×30.0 mm or 10 μm, 250×50.0 mm or Gemini C₆-phenyl 5.0 μm,21.2×150 mm or Synergi Fusion-RP 4.0 μm, 21.2×150 mm); mobile phase A:0.1% trifluoroacetic (or formic acid) in water, B: 0.1% trifluoroacetic(or formic acid) in acetonitrile. Chiral resolutions of racemic mixtureswere conducted on Varian HPLC systems (system 1, analytical:Varian/Dynamax pumps SD200, Varian Prostar autosampler 400 or 410,Varian Prostar PDA detector 335 and Varian Prostar CVM 500; system 2,preparative: Varian/Dynamax pumps SD200, Varian/Dynamax detector UVD-II) using Daicel Chiralpak IC columns (4.6×150 mm or 20.0×250 mm).Microwave-mediated reactions were performed using a Biotage Initiator™Synthesis System and using the standard 2 mL, 5 mL or 20 mL vials andlids. Preparative and analytical TLC were performed using AnaltechSilica gel GF plates.

Section A Preparation of Key Synthetic Intermediates

Intermediate A-2: methyl2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate—step a1

Trimethyl phosphonoacetate (78.6 mL, 485.0 mmol) was added to a 0° C.solution of 4-(4-hydroxyphenyl)cyclohexanone A-1 (76.9 g, 404.0 mmol) intetrahydrofuran (3.0 L) in a flame-dried 5.0 L 3-neck round bottom flaskequipped with mechanical stirrer and placed under an atmosphere ofnitrogen. Sodium hydride (60% in mineral oil, 37.2 g) was addedportionwise so that the internal temperature was maintained below 10° C.The reaction mixture was stirred at 0° C. for 20 mins and slowly warmedto room temperature and stirred for an additional 2.5 h. Afterdisappearance of starting material on TLC (3:7 hexanes:ethyl acetate),the reaction mixture was quenched with water (200 mL), then concentratedunder reduced pressure to a volume of ca. 1.5 L and diluted with water(500 mL). The aqueous layer was extracted with ethyl acetate (3×800 mL).The combined extracts were dried with anhydrous sodium sulfate andmagnesium sulfate, filtered, and concentrated to dryness under reducedpressure to give methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene)acetateA-2 (110.0 g; Yield=100%) as a white solid. MS (ESI) [M+1]⁺ 247.

Intermediate A-3: methyl 2-(4-(4-hydroxyphenyl)cyclohexyl)acetate—stepa2

Into a 2.5 L hydrogenation flask, a solution of methyl2-(4-(4-hydroxyphenyl)cyclohexylidene)acetate A-2 (53.14 g, 215.8 mmol)in ethyl acetate (1.0 L) was degassed and placed under an atmosphere ofnitrogen. A slurry of palladium on carbon (10% Pd, 5.3 g) in ethylacetate (20 mL) was then added under an atmosphere of nitrogen. Thereaction was subjected to a 35 psi hydrogen atmosphere using a ParrShaker overnight, then filtered over a celite pad, and the celite waswashed with ethyl acetate. The filtrate was concentrated to drynessunder reduced pressure and dried under high vacuum to give methyl2-(4-(4-hydroxyphenyl)cyclohexyl)acetate A-3 as a white solid (mixtureof cis and trans isomers, 53.5 g; Yield=99%). MS (ESI) [M+1]⁺ 249.

Intermediate trans-A-3: methyl2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate—step a3

Methyl 2-(4-(4-hydroxyphenyl)cyclohexyl)acetate A-3 (mixture of cis andtrans isomers, 107.0 g, 430.9 mmol) was dissolved in hot ethyl acetate(90.0 mL) and the solution was allowed to cool slowly to roomtemperature and to stand overnight to crystallize. The white crystalswere isolated by filtration, washed with an ice-cold mixture of ethylacetate:hexanes (15:85, 100 mL) and dried to give pure isomer trans-A-3(36.8 g). The mother liquors were concentrated to dryness under reducedpressure, and the solid residue was dissolved in a hot mixture of ethylacetate:hexanes (1:1, 90.0 mL). The solution was allowed to cool slowlyto room temperature and to stand overnight to crystallize. The colorlesssolid was isolated by filtration, washed with an ice-cold mixture ofethyl acetate:hexanes (15:85, 100 mL) and dried to give additional pureisomer trans-A-3 (8.60 g). Both crops were combined to give methyl2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetate trans-A-3 (45.4 g;Yield=42.4%; Purity=100%) as a white solid. MS (ESI) [M+1]⁺ 249.

Intermediate cis-A-3: methyl2-((1s,4s)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate—stepa3

The mother liquors resulting from the preparation of trans-A-3 wereconcentrated to dryness under reduced pressure. The solid residue (10.0g, 430.9 mmol) was dissolved in ethyl acetate (200 mL), and the solutionwas allowed to stand overnight at room temperature to crystallize. Thewhite crystals were isolated by filtration, washed with an ice-coldmixture of ethyl acetate:hexanes (15:85, 20 mL). The filtrate wasconcentrated to dryness under reduced pressure, and the residual solidwas recrystallized from ethyl acetate:hexanes (20:80, 10 mL) to giveisomer cis-A-3. This procedure was repeated seven times, and thecombined solids were finally washed with hexanes (100 mL) and driedunder high vacuum to give methyl2-((1s,4s)-4-((4-hydroxyphenyl)cyclohexyl)acetate cis-A-3 (500 mg;Yield=4%) as white crystals. MS (ESI) [M+1]⁺249.

Intermediate A-4: methyl2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetate—stepa4

Triethylamine (10.1 mL, 72.5 mmol) and trifluoromethanesulfonicanhydride (19.0 g, 67.3 mmol) were successively added dropwise to asolution of methyl 2-((1r,4r)-4-(4-hydroxyphenyl)cyclohexyl)acetatetrans-A-3 (12.0 g, 48.3 mmol) in methylene chloride (100.0 mL) at 0° C.The reaction was stirred under a nitrogen atmosphere for 5 h, thenpoured into a saturated aqueous solution of NaHCO₃ (150 mL) andextracted with methylene chloride. The combined extracts were washedwith brine, dried over anhydrous magnesium sulfate and concentrated to ahalf volume. The solution was then filtered through a short path silicagel column, rinsed with methylene chloride and concentrated to drynessunder reduced pressure to give methyl2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetateA-4 (18.0 g; Yield=98%). MS (ESI) [M+1]⁺ 381.

Intermediate trans-A-5: methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate—stepa5

Potassium acetate (15.5 g, 158 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complexwith dichloromethane (1:1) were successively added at room temperatureto a solution of methyl2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)cyclohexyl)acetateA-4 (12.0 g, 31.5 mmol) and bis(pinacolato)diboron (9.61 g, 37.8 mmol)in 1,4-dioxane (200.0 L). The reaction was degassed under reducedpressure several times, placed under an atmosphere of nitrogen andstirred at 80° C. for 17 h. After completion, the reaction mixture wascooled, filtered through a short path silica gel column and eluted withethyl acetate (450 mL). The solvent was removed under reduced pressure,and the crude brown oil was purified by flash column chromatography onsilica gel (3:1 hexanes:ethyl acetate) to give methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetatetrans-A-5 as a white solid (11.0 g; Yield=100%). MS (ESI) [M+1]⁺ 359.

Intermediate cis-A-5: methyl2-((1s,4s)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetate—stepa4 & a5

Intermediate cis-A-5 was prepared by the sequence step a-4-step a5described for intermediate methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetatetrans-A-5, by using methyl2-((1s,4s)-4-(4-hydroxyphenyl)cyclohexyl)acetate cis-A-3 as startingmaterial. MS (ESI) [M+1]⁺ 359.

Intermediate A-6:4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenylboronic acid—step a6

Sodium metaperiodate (896.0 mg, 4.19 mmol) was added at room temperatureto a solution of methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetatetrans-A-5 (500.0 mg, 1.40 mmol) in a 4:1 mixture of tetrahydrofuran andwater (11.2 mL) and the reaction mixture was stirred at room temperaturefor 30 mins. Then, a 1 N aqueous solution of hydrogen chloride (1.12 mL)was added, and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate (50 mL)and water (10 mL), then decanted, and the aqueous layer was extractedwith ethyl acetate (3×100 mL). The combined organic extracts weresuccessively washed with water (70 mL) then brine (70 mL), dried overanhydrous sodium sulfate, filtered and concentrated to dryness underreduced pressure. The solid residue was then washed with small amountsof hexanes (30 mL total) and dried under high vacuum to give4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenylboronic acid A-6(0.293 g; Yield=75%) as a white solid. MS (ESI) [M+1]⁺ 277.

Intermediate A-7: potassiumtrifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borate—stepa7

Potassium hydrogen difluoride (2.90 g, 37.08 mmol) was added at roomtemperature to a solution of methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetatetrans-A-5 (6.16 g, 14.83 mmol) in a 2:1 mixture of water and methanol(37.0 mL). The reaction was stirred at room temperature in apolypropylene reactor for 2 h. The reaction mixture was concentrated todryness under reduced pressure, the resulting solid residue wassuspended in ice-cold water (150 mL), quickly filtered, washed withice-cold diethyl ether (250 mL) and dried under high vacuum to givepotassiumtrifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borateA-7 as a white solid (4.79 g; Yield=95%). ¹H NMR (500 MHz, DMSO-d₆) δ(ppm) 1.11 (dq, J=2.68, 12.61 Hz, 2H), 1.52 (dq, J=2.68, 12.60 Hz, 2H),1.68-1.81 (m, 5H), 2.24 (d, J=6.80 Hz, 2H), 2.33 (tt, J=2.99, 12.29 Hz,1H), 3.60 (s, 3H), 6.93 (d, J=7.41 Hz, 2H), 7.22 (d, J=7.41 Hz, 2H).

Intermediate A-9: 1-(4-bromophenyl)piperazine—step a8

A solution of bis(2-chloroethyl)amine (4.0 g, 30.0 mmol), p-bromoanilineA-8 (5.0 g, 30.0 mmol) and potassium carbonate (4.0 g, 30.0 mmol) indiethylene glycol dimethyl ether (106 mL) was heated to reflux for 2days. The reaction mixture was quenched with water (50 mL), and the pHwas adjusted to pH 10 with a 1 N aqueous solution of NaOH (5 mL). Theresulting mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated to dryness under reduced pressure.The crude residue was purified by flash column chromatography on silicagel (10:1 methylene chloride:methanol) to give1-(4-bromophenyl)piperazine A-9 (5.1 g; Yield=70%). MS (ESI) [M+1]⁺ 241.

Intermediate A-10: methyl2-(4-(4-bromophenyl)piperazin-1-yl)acetate—step a9

N,N-diisopropylethylamine (4.3 mL, 25.0 mmol), potassium carbonate (1.7g, 12.0 mmol) and chloroacetic acid methyl ester (1.4 g, 12.0 mmol) weresuccessively added at room temperature to a solution of1-(4-bromophenyl)piperazine A-9 (3.0 g, 12.0 mmol) in tetrahydrofuran(22.6 mL) and N,N-dimethylformamide (10.6 mL). The reaction mixture wasstirred overnight at room temperature and quenched with water (50 mL).The aqueous layer was extracted with ethyl acetate (3×50 mL), and thecombined extracts were dried over anhydrous magnesium sulfate andconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography on silica gel (10:1 hexanes:ethylacetate) to give methyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate A-10(2.0 g; Yield=50%). MS (ESI) [M+1]⁺ 241.

Intermediate A-11: methyl2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)acetate—stepa10

Methyl 2-(4-(4-bromophenyl)piperazin-1-yl)acetate A-10 (240.0 mg, 1.00mmol), bis(pinacolato)diboron (292.0 mg, 1.20 mmol), potassium acetate(376.0 mg, 3.83 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (39.1 mg, 0.048 mmol) were mixed in 1,4-dioxane(20 mL). The reaction mixture was degassed under reduced pressure threetimes, placed under an atmosphere of nitrogen and stirred at 80° C. for17 h. After completion, the reaction mixture was cooled, filteredthrough a celite pad, washed with ethyl acetate (450 mL) andconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography on silica gel (1:1 hexanes:ethyl acetate)to give methyl2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)acetateA-11 (0.25 g; Yield=70%). MS (ESI) [M+1]⁺ 361.

Intermediate A-13: (1R,2R)-methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)cyclopentanecarboxylate—stepa11

(1R,2R)-methyl-2-(4-bromobenzoyl)cyclopentane-carboxylate A-12 (775.0mg, 2.50 mmol), bis(pinacolato)diboron (734.0 mg, 2.89 mmol), potassiumacetate (0.757 g, 7.71 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (78.7 mg, 0.096 mmol) were mixed in1,4-dioxane (40.0 mL). The reaction mixture was degassed under reducedpressure three times, placed under an atmosphere of nitrogen and stirredat 80° C. for 17 h. After completion, the reaction mixture was cooled,filtered through a celite pad, washed with ethyl acetate (300 mL) andconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography on silica gel (1:1 hexanes:ethyl acetate)to give (1R,2R)-methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)cyclopentanecarboxylateA-13 (0.56 g; Yield=80%). MS (ESI) [M+1]⁺ 359.

Intermediate A-15: 6-bromo-N-phenyl-1H-indole-3-carboxamide—step a12

N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1.34 g, 4.16 mmol) was added at 0° C. to a solutionof 6-bromo-1H-indole-3-carboxylic acid A-14 (1.0 g, 4.00 mmol), aniline(0.476 mL, 5.23 mmol) and N-ethyl-N,N-diisopropylamine (0.726 mL, 4.16mmol) in N,N-dimethylformamide (10.0 mL). The reaction mixture wasstirred overnight at room temperature and then quenched with water (50mL). The aqueous layer was extracted with methylene chloride (2×60 mL).The combined extracts were dried over anhydrous magnesium sulfate,filtered, and concentrated to dryness under reduced pressure. The crudebrown oil was purified by flash column chromatography on silica gel (1:1hexanes:ethyl acetate) to give 6-bromo-N-phenyl-1H-indole-3-carboxamideA-15 as a white solid (0.90 g; Yield=70%). MS (ESI) [M+1]⁺ 315, 317.

Intermediate A-17:4-(benzo[d]oxazol-2-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine—stepa13

2-Chlorobenzoxazole (0.30 g, 2.0 mmol) was added to a solution of7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.42 g, 2.0 mmol) intoluene (10.0 mL) and N,N-dimethylformamide (2.0 mL). The reactionmixture was stirred overnight at 100° C. under an atmosphere of nitrogenand then concentrated to dryness under reduced pressure. The residue waspurified by flash column chromatography on silica gel (1:1 hexanes:ethylacetate) to give4-(benzo[d]oxazol-2-yl)-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine A-17(0.12 g; Yield=18%). MS (ESI) [M+1]⁺ 331, 333.

Intermediate A-19: 6-bromo-N-phenylquinazolin-2-amine—step a14

Trifluoroacetic acid (0.23 mL, 3.0 mmol) was added at room temperatureto a solution of 6-bromo-2-iodoquinazoline A-18 (0.50 g, 1.0 mmol) andaniline (0.16 mL, 1.8 mmol) in isopropyl alcohol (6.36 mL). The reactionmixture was heated at 70° C. for 12 h, then cooled, quenched withtriethylamine (1.0 mL) and concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography onsilica gel (97:3 methylene chloride:methanol) to give6-bromo-N-phenylquinazolin-2-amine A-19 (0.20 g; Yield=68%). MS (ESI)[M+1]⁺ 300, 302.

Intermediate A-21: 5-bromo-N-phenyl-1H-indole-1-carboxamide—step a15

Sodium hydride (60% dispersion in mineral oil, 130.0 mg, 5.4 mmol) wasadded to a solution of 5-bromoindole A-20 (975.0 mg, 5.0 mmol) inN,N-dimethylformamide (30 mL) at 0° C. The reaction mixture was thenstirred at room temperature for 3 h and phenyl isocyanate (0.54 mL, 4.9mmol) was added dropwise. The reaction mixture was stirred at roomtemperature overnight and concentrated to dryness under reducedpressure. The residue was partitioned between a 1 N aqueous hydrogenchloride solution (50 mL) and ethyl acetate (50 mL), and the aqueouslayer was separated then extracted with ethyl acetate (3×100 mL). Thecombined organic extracts were successively washed with water thenbrine, dried over anhydrous sodium sulfate, filtered and concentrated todryness under reduced pressure. The residue was purified by flash columnchromatography on silica gel (1:1 hexanes:ethyl acetate) to give5-bromo-N-phenyl-1H-indole-1-carboxamide A-21 as yellow solid (0.88 g;Yield=56%). MS (ESI) [M+1]⁺ 315, 317.

Intermediate A-23: 6-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one—stepa16

1,8-Diazabicyclo[5.4.0]undec-7-ene (140.0 μL, 0.94 mmol) was added atroom temperature to a solution of 3-amino-6-bromopyridin-2-ol A-22(178.0 mg, 0.94 mmol) and methyl 2-bromoacetate (81.0 μL, 0.86 mmol) inanhydrous 1-methylpyrrolidin-2-one (3.76 mL) under an argon atmosphere,in a 10 mL microwave reactor vial. The sealed reaction mixture washeated at 180° C. for 3 mins under microwave irradiation and thendiluted with ethyl acetate (30 mL). The organic layer was washed withbrine (3×50 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness under reduced pressure. The crude residue waspurified by flash column chromatography on silica gel (hexanes:ethylacetate gradient) to give 6-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-oneA-23 (95.7 mg, Yield=45%). MS (ESI), [M+1]⁺ 229, 231.

Intermediate A-24: 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine—stepa17

Borane dimethyl sulfide complex (1 M solution in THF, 0.82 mL, 0.82mmol) was added at room temperature to a solution of6-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one A-23 (95.7 mg, 0.41 mmol)in anhydrous THF (1.23 mL) under an atmosphere of argon. The reactionmixture was heated to reflux for 2 h, cooled to room temperature,quenched with methanol (3 mL), stirred for 40 mins and concentrated todryness under reduced pressure. The crude light beige solid6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine A-24 (91.5 mg,Yield=ca. 95%) was used as such for the next step. MS (ESI), [M+1]⁺ 215,217.

Intermediate A-25:6-bromo-N-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide—stepa18

Phenyl isocyanate (90.0 μL, 0.82 mmol) was added at room temperature toa solution of 6-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine A-24(91.5 mg, 0.41 mmol) in 3:1 anhydrous methylenechloride:dimethylsulfoxide (2.0 mL) under argon. The reaction mixturewas stirred at room temperature for 12 h, quenched with methanol (2.0mL) and diluted with methylene chloride (10 mL). The heavy precipitateformed was isolated by filtration, washed with small portions ofmethylene chloride and dried under high vacuum to give6-bromo-N-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamideA-25 (74.8 mg, Yield=55% over 2 steps). MS (ESI), [M+1]⁺ 334, 336.

Intermediate A-27: 6-bromo-N-phenylquinoxalin-2-amine—step a19

6-Bromo-2-chloroquinoxaline A-26 (0.20 g, 0.821 mmol), aniline (97 μL,1.07 mmol) and N-ethyl-N,N-diisopropylamine (214 μL, 1.23 mmol) weremixed in 1-methylpyrrolidin-2-one (4.11 mL) in a 5 mL microwave reactorvial under an argon atmosphere. The reaction mixture was heated at 180°C. for 30 mins, then at 200° C. for 20 mins under microwave irradiation.The mixture was then cooled to room temperature, diluted with ethylacetate (30 mL), quenched with water (20 mL) and decanted. The aqueouslayer was extracted with ethyl acetate (2×40 mL); the combined organicextracts were then successively washed with water (30 mL), brine (30mL), dried over anhydrous magnesium sulfate, filtered and concentratedto dryness under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (100:0 to 0:100 gradient ofmethylene chloride:ethyl acetate) to give6-bromo-N-phenylquinoxalin-2-amine A-27 (0.13 g; Yield=53%). MS (ESI)[M+1]⁺ 300, 302.

Intermediate A-29: 4-bromo-2-(2-methylallyloxy)-1-nitrobenzene—step a20

Potassium bis(trimethylsilyl)amide (solution in toluene, 5.0 mL, 2.5mmol) was added dropwise to a solution of4-bromo-2-fluoro-1-nitrobenzene A-28 (500 mg, 2.273 mmol) and2-methylprop-2-en-1-ol (dried before use over 4 Å MS, 0.212 mL, 2.50mmol) in anhydrous THF (6.4 mL) at 0° C. under an atmosphere of argon.The reaction mixture was allowed to stir at room temperature for 12 h,then diluted with methylene chloride (50 mL), quenched with a saturatedaqueous solution of NH₄Cl (30 mL) and decanted. The aqueous layer wasextracted with methylene chloride (2×50 mL); the combined organicextracts were then washed with brine (2×40 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography onsilica gel (90:10 to 0:100 gradient of hexanes:ethyl acetate) to give4-bromo-2-(2-methylallyloxy)-1-nitrobenzene A-29 (496 mg; Yield=80%). MS(ESI) [M+1]⁺ 272, 274.

Intermediate A-30:1-(5-bromo-2-nitrophenoxy)propan-2-one—step a21

A solution of 4-bromo-2-(2-methylallyloxy)-1-nitrobenzene A-29 (495 mg,1.82 mmol) in anhydrous methanol (35 mL) was treated at −78° C. withozone until a persistent blue color was observed. The ozone bubbling wasthen stopped. The reaction mixture was bubbled with nitrogen gas for 30mins, and then dimethyl sulfide (2.25 mL, 30.6 mmol) was added at −78°C. The solution was allowed to warm to room temperature overnight beforeconcentrating to dryness. The resulting oily residue was dissolved inacetone (17.5 mL) and stirred at room temperature for 18 h over wetamberlyst 15 resin (2.50 g). The solution was then filtered andconcentrated to dryness. The crude residue was dissolved in diethylether (200 mL) and methylene chloride (20 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated to dryness under reducedpressure to give a yellow solid. Recrystallization from pentane (200 mL)gave 1-(5-bromo-2-nitrophenoxy)propan-2-one A-30 (400.2 mg; Yield=80%over 2 steps) as a light tan solid. MS (ESI) [M+1]⁺ 274, 276.

Intermediate A-31:7-bromo-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step a22

A slurry of Raney nickel in water (ca. 15 mg) was suspended in ethylacetate (5 mL) in a round-bottom flask and carefully concentrated todryness by heating at 30° C. under reduced pressure. The procedure wasrepeated with toluene (10 mL) and the dry metal was then kept under anargon atmosphere. A solution of 1-(5-bromo-2-nitrophenoxy)propan-2-oneA-30 (30.0 mg, 0.11 mmol) in dry ethyl acetate (0.54 mL) and absoluteethanol (0.54 mL) was added at room temperature to the Raney nickel, andthe reaction mixture was heated at 50° C. for 12 h under an atmosphereof hydrogen. The solution was then placed under a nitrogen atmosphere,filtered over a celite pad while blanketing under nitrogen and rinsingwith ethyl acetate (20 mL), and concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography onsilica gel (90:10 to 0:100 gradient of hexanes:ethyl acetate) to give7-bromo-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine A-31 (14.0 mg;Yield=56%). MS (ESI) [M+1]⁺ 228, 230.

Intermediate (R)-A-33: (R)-methyl2-(5-bromo-2-nitrophenoxy)propanoate—step a23

Triphenylphosphine (624.0 mg, 2.38 mmol) was added at room temperatureto a solution of 5-bromo-2-nitrophenol A-32 (400.0 mg, 1.83 mmol) andmethyl(−)-(S)-lactate (0.149 mL, 1.56 mmol) in anhydrous methylenechloride (18.3 mL) under an atmosphere of argon. After 10 mins ofstirring, the reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (0.360 mL, 1.83 mmol) was added dropwise. The orangesolution was warmed to room temperature, stirred for 12 h, thenconcentrated to ca. 1.0 mL, diluted with pentane (7 mL) and diethylether (8 mL), filtered and rinsed with diethyl ether-pentane (15 mL).The filtrate was concentrated to dryness under reduced pressure, and theresidue was purified by flash column chromatography on silica gel(hexanes:ethyl acetate gradient) to give (R)-methyl2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-33 as a yellow solid (525.0mg; Yield=94%). MS (ESI) [M+1]⁺ 304, 306.

Intermediate (R)-A-34:(R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one—step a24

Iron powder (1.91 g, 34.15 mmol) and (R)-methyl2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-33 (525.0 mg, 1.71 mmol) wereheated at 50° C. in glacial acetic acid (10.5 mL) for 5 h. The reactionmixture was cooled to room temperature, diluted with ethyl acetate (80mL), filtered over a pad of celite, and rinsed with ethyl acetate (80mL). The filtrate was successively washed with water (2×30 mL), asaturated aqueous solution of sodium bicarbonate (40 mL), then driedover anhydrous magnesium sulfate, filtered and concentrated to drynessunder reduced pressure. The resulting white crystalline solid(R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (R)-A-34 (399.4mg, Yield=96%) was used as such for the next step without purification.MS (ESI) [M+1]⁺ 242, 244.

Intermediate (R)-A-35:(R)-7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step a17

Intermediate (R)-A-35 was prepared by the procedure described for stepa17, using (R)-7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one(R)-A-34 as starting material. MS (ESI) [M+1]⁺ 228, 230; ee=96%(rt=5.195 min for (R)-A-35, rt=6.283 min for (S)-A-35; using DaicelChiralpak AD column (4.6×150 mm) on Varian HPLC system 1 and elutingwith 10% ethanol in hexanes:diethylamine 99.5:0.5, isocratic gradient at1 mL/min).

Intermediate A-36: methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)propanoate—stepa25

Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 0.67 mL) wasadded dropwise to a solution of methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetatetrans-A-5 (179.0 mg, 0.50 mmol) in anhydrous THF (10.0 mL) at −78° C.under an atmosphere of argon. The reaction was stirred at −78° C. for 1h, then methyl iodide (42.0 μL, 0.67 mmol) was added. The reaction wasallowed to warm to room temperature and stirred overnight at roomtemperature, then successively quenched with water (5 mL), diluted withethyl acetate (15 mL) and decanted. The aqueous layer was extracted withethyl acetate (3×30 mL); the combined organic extracts were successivelywashed with water (30 mL), brine (30 mL), then dried over anhydrousmagnesium sulfate and concentrated to dryness under reduced pressure.The crude residue was purified by flash column chromatography on silicagel (hexanes:ethyl acetate gradient) to give methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)propanoateA-36 (119.0 mg, Yield=80%). MS (ESI), [M+1]⁺ 373.

Section B Preparation of Example Compounds

Intermediate B-2: 5-bromo-N-phenylindoline-1-carboxamide—step b1

Phenyl isocyanate (5.90 g, 5.0 mmol) was added dropwise to a solution of5-bromoindoline B-1 (1.0 g, 5.0 mmol) in methylene chloride (10.0 mL).The reaction was stirred at room temperature overnight and concentratedto dryness under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (1:1 hexanes:ethyl acetate) to give5-bromo-N-phenylindoline-1-carboxamide B-2 as white solid (1.5 g;Yield=95%). MS (ESI) [M+1]⁺ 317, 319.

Intermediate B-3: methyl2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate—stepb2

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (20.0 mg, 0.025 mmol) and an aqueous solution ofsodium carbonate (307.0 mg, 2.9 mmol in 1.0 mL of water) were added to asolution of 5-bromo-N-phenylindoline-1-carboxamide B-2 (177.1 mg, 0.558mmol) and methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetatetrans-A-5 (300.0 mg, 0.840 mmol) in isopropanol (5.0 mL). The reactionwas degassed several times under reduced pressure, placed under anitrogen atmosphere and stirred at 80° C. for 10 h. After cooling, themixture was filtered through a celite pad, washed with ethyl acetate(100 mL) and concentrated to dryness under reduced pressure. The residuewas purified by flash column chromatography on silica gel (1:1hexanes:ethyl acetate) to give methyl2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetateB-3 (160.0 mg; Yield=61%). MS (ESI) [M+1]⁺ 469.

Example B-4:2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid—step b3

Lithium hydroxide monohydrate (16.8 mg, 0.4 mmol) was added to asolution of methyl2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetateB-3 (46.9 mg, 0.1 mmol) in tetrahydrofuran (10.0 mL) and water (1.0 mL).The reaction was stirred at room temperature overnight and quenched withan aqueous solution of hydrogen chloride (1 N, 1.0 mL). The reaction wasconcentrated to dryness under reduced pressure, and the residue waspurified by flash column chromatography on C₁₈ reverse phase(water:acetonitrile gradient with 0.05% formic acid) to give2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid B-4 (24.1 mg; Yield=53%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (q,J=11.65 Hz, 2H), 1.53 (q, J=11.65 Hz, 2H), 1.75 (br s, 1H), 1.78-1.90(m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.53-2.55 (m, 1H), 3.22 (t, J=8.51 Hz,2H), 4.18 (t, J=8.51 Hz, 2H), 7.02 (t, J=7.25 Hz, 1H), 7.25-7.35 (m,5H), 7.38-7.63 (m, 5H), 7.91 (d, J=8.20 Hz, 1H), 8.55 (s, 1H); MS (ESI)[M+1]⁺ 455.

Intermediate B-5: methyl2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate—step b4

5-Bromoindoline B-1 (595.0 mg, 3.00 mmol), potassiumtrifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borateA-7 (1.12 g, 3.31 mmol), anhydrous potassium carbonate (1.37 g, 9.92mmol) and palladium (II) acetate (75.0 mg, 0.33 mmol) were mixed inanhydrous methanol (12.0 mL) in a 20 mL microwave reactor vial,evacuated several times and placed under an argon atmosphere. The sealedreaction mixture was heated at 65° C. for 45 mins under microwaveirradiation and then diluted with methylene chloride (100 mL) and water(100 mL). The aqueous layer was separated and extracted with methylenechloride (3×100 mL). The combined organic extracts were successivelywashed with an aqueous pH 7 phosphate buffer solution (70 mL) then brine(80 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (methylene chloride:ethyl acetate gradient)to give methyl 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetateB-5 as a light yellow oil (830.0 mg, Yield=75%). MS (ESI), [M+1]⁺ 350.

Intermediate B-6: methyl2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetate—stepb5

3,4-Difluorophenyl isocyanate (198.0 mg, 1.28 mmol) was added under anatmosphere of argon to a solution of methyl2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 (90.0 mg,0.255 mmol) in anhydrous methylene chloride (1.27 mL) at roomtemperature. The reaction mixture was stirred overnight, thenconcentrated to dryness under reduced pressure to give methyl2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetateB-6 as a crude solid residue (160.0 mg), sufficiently pure to be usedfor the next step without additional purification. MS (ESI), [M+1]⁺ 505.

Example B-7:2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid—step b6

Lithium hydroxide monohydrate (107.0 mg, 2.55 mmol) was added to asolution of methyl2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)acetateB-6 (160.0 mg, 0.255 mmol) in a 1:1:1 mixture oftetrahydrofuran:water:methanol (5.10 mL) at room temperature. After 12 hof vigorous stirring, the reaction mixture was diluted with water (40mL) and washed with methylene chloride (50 mL). The aqueous layer wasthen acidified to pH 0 with a 1 N aqueous hydrogen chloride solution (5mL) and extracted with ethyl acetate (3×50 mL). The combined extractswere dried over anhydrous magnesium sulfate and concentrated to drynessunder reduced pressure. The crude residue was purified by flash columnchromatography on C₁₈ reverse phase (water:acetonitrile gradient with0.05% formic acid) to give2-((1r,4r)-4-(4-(1-(3,4-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid B-7 (68.8 mg, Yield=55% over 2 steps). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.04-1.24 (m, 2H), 1.41-1.62 (m, 2H), 1.74 (m, 1H), 1.77-1.86 (m,4H), 2.15 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.23 (t, J=8.20 Hz, 2H),4.15 (t, J=8.20 Hz, 2H), 7.27 (d, J=7.57 Hz, 2H), 7.34-7.40 (m, 2H),7.42 (d, J=8.20 Hz, 1H), 7.48 (s, 1H), 7.52 (d, J=7.57 Hz, 2H), 7.74 (m,1H), 7.91 (d, J=7.88 Hz, 1H), 8.76 (br s, 1H), 12.08 (br s, 1H); MS(ESI), [M+1]⁺ 491.

Intermediate B-8: methyl2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetate—stepb7

Pyrrolidine-1-carbonyl chloride (77.3 μL, 0.70 mmol) was added under anargon atmosphere to a solution of methyl2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 (53.0 mg,0.140 mmol), N,N-dimethylaminopyridine (8.6 mg, 0.07 mmol) andtriethylamine (194.0 μL, 1.40 mmol) in anhydrous methylene chloride(1.04 mL). The reaction mixture was stirred overnight at roomtemperature and then heated for 5 h at 50° C. Upon cooling to roomtemperature, it was then diluted with ethyl acetate (30 mL) and quenchedwith an aqueous pH 7 phosphate buffer solution (30 mL). The aqueouslayer was extracted with ethyl acetate (3×40 mL); the combined organicextracts were successively washed with an aqueous pH 7 phosphate buffersolution (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (methylenechloride:ethyl acetate gradient) to give methyl2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetateB-8 (43.8 mg, Yield=70%). MS (ESI) [M+1]⁺ 447.

Example B-9:2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid—step b3

Example B-9 was prepared by the procedure described for step b3, usingmethyl2-((1r,4r)-4-(4-(1-(pyrrolidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)acetateB-8 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q,J=11.45 Hz, 2H), 1.49 (q, J=11.40 Hz, 2H), 1.70-1.78 (m, 1H), 1.84 (m,8H), 2.15 (d, J=6.94 Hz, 2H), 2.48 (m, 1H), 3.10 (t, J=8.35 Hz, 2H),3.38 (m, 4H), 3.94 (t, J=8.35 Hz, 2H), 7.21 (d, J=8.20 Hz, 1H), 7.27 (d,J=7.57 Hz, 2H), 7.37 (d, J=8.20 Hz, 1H), 7.46 (s, 1H), 7.51 (d, J=7.25Hz, 2H), 12.20 (br s, 1H); MS (ESI) [M+1]⁺ 433.

Intermediate B-10: (S)-tert-butyl2-(5-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carboxylate—stepb8

Triethylamine (159 μL, 1.144 mmol) was added at room temperature to asolution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid(92.3 mg, 0.429 mmol), methyl2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)acetate B-5 (100.0 mg,0.286 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (217.5 mg, 0.572 mmol) in anhydrousN,N-dimethylformamide (2.98 mL) under an atmosphere of nitrogen. Thereaction mixture was stirred overnight, then partitioned betweenmethylene chloride (30 mL) and an aqueous solution of pH 7 phosphatebuffer (30 mL). The aqueous layer was extracted with methylene chloride(3×30 mL); the combined extracts were successively washed with anaqueous solution of pH 7 phosphate buffer (30 mL), brine (30 mL), thendried over anhydrous magnesium sulfate and concentrated to dryness underreduced pressure. The crude residue was purified by flash columnchromatography on silica gel (methylene chloride:ethyl acetate gradient)to give (S)-tert-butyl2-(5-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carboxylateB-10 (128.4 mg, Yield=78%). MS (ESI) [M+1]⁺ 547.

Example B-11:2-((1r,4r)-4-(4-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid—step b3

Example B-11 was prepared by the procedure described for step b3, using(S)-tert-butyl2-(5-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carboxylateB-10 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (m, 2H),1.25 (s, 6H), 1.40 (s, 3H), 1.48 (m, 2H), 1.70-1.95 (m, 8H), 2.15 (d,J=6.62 Hz, 2H), 2.29 (m, 1H), 2.48 (t, J=11.80 Hz, 1H), 3.23 (m, 2H),3.32-3.47 (m, 2H), 4.17 (m, 2H), 4.49 (dd, J=7.25 Hz, J=8.20 Hz, 0.6H),4.56 (br d, J=7.90 Hz, 0.4H), 7.28 (d, J=7.88 Hz, 2H), 7.46 (t, J=8.90Hz, 1H), 7.50-7.57 (m, 3H), 8.10 (d, J=8.20 Hz, 0.4H), 8.14 (d, J=8.20Hz, 0.6H), 12.11 (br s, 1H); MS (ESI) [M+1]⁺ 533.

Example B-12:2-((1r,4r)-4-(4-(1-((S)-pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid—step b9

A solution of2-((1r,4r)-4-(4-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid B-11 (75.0 mg, 0.141 mmol) in methylene chloride (1.10 mL) and 4 Nhydrogen chloride in 1,4-dioxane (1.05 mL) was stirred at roomtemperature for 12 h, then heated to 45° C. for 2 h. The reactionmixture was then partitioned between methylene chloride (40 mL) andwater (40 mL) and separated. The aqueous layer was extracted with ethylacetate (3×40 mL); the combined organic extracts were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Thecrude residue (43.1 mg) contained 90% pure B-12. The aqueous layer wasconcentrated under reduced pressure to a volume of ca 2 mL, thenfiltered. The solid collected was washed with water (5 mL) then ethylacetate (5 mL) and dried under high vacuum to give pure2-((1r,4r)-4-(4-(1-((S)-pyrrolidine-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid B-12 as white crystals (32.8 mg, Yield=54%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.14 (q, J=11.45 Hz, 2H), 1.50 (q, J=11.50 Hz, 2H),1.70-1.89 (m, 5H), 1.92-2.04 (m, 3H), 2.16 (d, J=6.62 Hz, 2H), 2.48 (m,1H), 3.28 (t, J=8.50 Hz, 2H), 3.21-3.31 (m, 3H), 4.14 (q, J=8.83 Hz,1H), 4.26 (q, J=8.72 Hz, 1H), 4.59 (m, 1H), 7.31 (d, J=7.88 Hz, 2H),7.50-7.62 (m, 4H), 8.11 (d, J=8.20 Hz, 1H), 8.65 (br s, 1H), 12.06 (brs, 1H); MS (ESI) [M+1]⁺ 433.

Intermediate B-14:7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one—step a16

Intermediate B-14 was prepared by the procedure described for step a16,using 2-amino-5-bromophenol B-13 and ethyl 2-bromopropanoate as startingmaterials. MS (ESI) [M+1]⁺ 242, 244.

Intermediate B-15:7-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step a17

Intermediate B-15 was prepared by the procedure described for step a17,using 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B-14 as startingmaterial. MS (ESI) [M+1]⁺ 228, 230.

Intermediate B-16: methyl2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb10

7-Bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine B-15 (50.0 mg,0.219 mmol), potassiumtrifluoro(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)borateA-7 (89.0 mg, 0.263 mmol), anhydrous potassium carbonate (76.0 mg, 0.548mmol) and[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride (PEPPSI-iPr, 20.0 mg, 0.022 mmol) were mixed in 1:1ethanol:water (1.10 mL) in a 5 mL microwave reactor vial, evacuatedseveral times and placed under an argon atmosphere. The reaction mixturewas sealed, heated at 65° C. for 50 mins under microwave irradiation andconcentrated to dryness under reduced pressure. The crude residue wasadsorbed on silica gel (5 g) and purified by flash column chromatographyon silica gel (dry loading, methylene chloride:ethyl acetate gradient)to give methyl2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-16 (47.8 mg, Yield=58%) as a clear oil. MS (ESI) [M+1]⁺ 380.

Intermediate B-17: methyl2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb5

Intermediate B-17 was prepared by the procedure described for step b5,using methyl2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-16 and phenyl isocyanate as starting materials. MS (ESI) [M+1]⁺ 499.

Example B-18:2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid—step b6

Example B-18 was prepared by the procedure described for step b6, usingmethyl2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-17 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q,J=11.50 Hz, 2H), 1.36 (d, J=6.31 Hz, 3H), 1.49 (q, J=11.70 Hz, 2H),1.70-1.78 (m, 1H), 1.83 (br d, J=10.20 Hz, 4H), 2.16 (d, J=6.62 Hz, 2H),2.47 (m, 1H), 3.36 (dd, J=7.57, 13.20 Hz, 1H), 4.10 (dd, J=2.20, 13.20Hz, 1H), 4.36 (br t, J=5.83 Hz, 1H), 7.01 (t, J=7.41 Hz, 1H), 7.12-7.19(m, 2H), 7.25-7.34 (m, 4H), 7.50 (d, J=8.20 Hz, 2H), 7.53-7.57 (m, 3H),9.17 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 485. The two enantiomerswere resolved by chiral HPLC (isocratic mode, 1 mL/min on Varian system1; 85:15 hexanes:isopropanol): enantiomer A (R absolute configuration,rt=13.93 min); enantiomer B (S absolute configuration, rt=18.27 min).

Intermediate B-19: methyl2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb10

Intermediate B-19 was prepared by the procedure described for step b10,using 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one B-14 as startingmaterial. MS (ESI) [M+1]⁺ 394.

Example B-20:2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid—step b6

Example B-20 was prepared by the procedure described for step b6, usingmethyl2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-19 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.08-1.18 (q,J=11.90 Hz, 2H), 1.45 (d, J=6.62 Hz, 3H), 1.45-1.50 (m, 2H), 1.70-1.78(m, 1H), 1.78-1.88 (m, 4H), 2.15 (d, J=6.94 Hz, 2H), 3.30-3.33 (m, 1H),4.70 (q, J=6.62 Hz, 1H), 6.94 (d, J=8.20 Hz, 1H), 7.22-7.31 (m, 4H),7.52 (d, J=8.20 Hz, 2H), 10.72 (s, 1H), 12.05 (br s, 1H); MS (ESI)[M+1]⁺ 380.

Example B-21:2-((1r,4r)-4-(4-(2-methyl-3-oxo-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid—step b11

Phenyl isocyanate (9.0 μL, 0.084 mmol) was added under argon to asolution of2-((1r,4r)-4-(4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid B-20 (28.9 mg, 0.076 mmol) and N,N-dimethylaminopyridine (2.0 mg,0.016 mmol) in anhydrous methylene chloride (0.5 mL) and anhydrous DMSO(0.5 mL) at room temperature. The reaction mixture was stirred overnightat room temperature, then additional phenyl isocyanate (9.0 μL, 0.084mmol) was added. The mixture was stirred for 24 h, concentrated to yielda crude DMSO solution, which was purified by flash column chromatographyon C₁₈ reverse phase (water:acetonitrile gradient with 0.05% formicacid) to give2-((1r,4r)-4-(4-(2-methyl-3-oxo-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid B-21 (4.7 mg, Yield=12%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12-1.21(m, 2H), 1.44 (d, J=6.65 Hz, 3H), 1.46-1.54 (m, 2H), 1.77-1.89 (m, 4H),2.24 (d, J=6.31 Hz, 2H), 2.45-2.50 (m, 1H), 3.31 (br s, 1H), 4.66-4.72(m, 1H), 6.94 (d, J=7.88 Hz, 1H), 7.00-7.04 (m, 1H), 7.22-7.32 (m, 6H),7.52 (d, J=7.88 Hz, 2H), 7.61 (d, J=7.88 Hz, 2H), 9.89 (s, 1H), 10.72(br s, 1H); MS (ESI) [M+1]⁺ 499.

Intermediate B-23:1-(4-bromo-2-fluorophenylamino)-2-methyl-1-oxopropan-2-yl acetate—stepb12

Triethylamine was added dropwise to a solution of4-bromo-2-fluoroaniline B-22 (600 mg, 3.158 mmol) and1-chloro-2-methyl-1-oxopropan-2-yl acetate (0.915 mL, 6.315 mmol) inanhydrous methylene chloride (10.2 mL) at room temperature. After 20mins, additional methylene chloride (10.2 mL) was added, and theresulting suspension was stirred at room temperature for 90 mins. Thereaction mixture was diluted with methylene chloride (50 mL), quenchedwith an aqueous pH 7 phosphate buffer solution (60 mL) and decanted. Theaqueous layer was extracted with methylene chloride (2×50 mL). Thecombined organic extracts were then successively washed with water (40mL) and brine (40 mL), dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The crude residue was purifiedby flash column chromatography on silica gel (methylene chloride:ethylacetate gradient) to give1-(4-bromo-2-fluorophenylamino)-2-methyl-1-oxopropan-2-yl acetate B-23as a white solid (956.0 mg, Yield=95%). MS (ESI) [M+1]⁺ 318, 320.

Intermediate B-24:1-(4-bromo-2-fluorophenylamino)-2-methylpropan-2-ol—step a17

Intermediate B-24 was prepared by the procedure described for step a17,using 1-(4-bromo-2-fluorophenylamino)-2-methyl-1-oxopropan-2-yl acetateB-23 as starting material. MS (ESI) [M+1]⁺ 262, 264.

Intermediate B-25:7-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine—step b13

A solution of 1-(4-bromo-2-fluorophenylamino)-2-methylpropan-2-ol B-24(97 mg, 0.35 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was addedvia syringe at room temperature to a suspension of sodium hydride (60%disp. in oil, 35.0 mg, 0.88 mmol) in anhydrous N,N-dimethylformamide(2.0 mL) under an atmosphere of argon. After 30 mins of vigorousstirring, the reaction mixture was heated at 65° C. overnight, followedby heating at 130° C. under microwave irradiation for 90 mins. Aftercooling to room temperature, the reaction mixture was diluted with ethylacetate (30 mL), quenched with an aqueous pH 7 phosphate buffer solution(25 mL) and decanted. The aqueous layer was extracted with ethyl acetate(3×30 mL); the combined organic extracts were then successively washedwith water (30 mL) and brine (30 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The cruderesidue was purified by flash column chromatography on silica gel(methylene chloride:ethyl acetate gradient) to give7-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine B-25 as paleyellow oil (39.1 mg, Yield=45%). MS (ESI) [M+1]⁺ 242, 244.

Intermediate B-26: methyl2-((1r,4r)-4-(4-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb10

Intermediate B-26 was prepared by the procedure described for step b10,using 7-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine B-25 asstarting material. MS (ESI) [M+1]⁺ 394.

Example B-27: methyl2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb5

Example B-27 was prepared by the procedure described for step b5, usingmethyl2-((1r,4r)-4-(4-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-26 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q,J=11.19 Hz, 2H), 1.34 (s, 6H), 1.49 (q, J=11.19 Hz, 2H), 1.73-1.86 (m,5H), 2.26 (d, J=6.62 Hz, 2H), 2.45-2.49 (m, 1H), 3.61 (s, 3H), 3.64 (s,2H), 7.00 (t, J=7.55 Hz, 1H), 7.11 (s, 1H), 7.16 (d, J=9.30 Hz, 1H),7.26-7.31 (m, 4H), 7.46 (d, J=8.19 Hz, 1H), 7.50 (d, J=8.36 Hz, 2H),7.55 (d, J=8.36 Hz, 2H), 9.23 (s, 1H); MS (ESI) [M+1]⁺ 513.

Example B-28:2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid—step b14

Lithium hydroxide monohydrate (12.1 mg, 0.29 mmol) was added to asolution of methyl2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-27 (ca. 100.0 mg, 0.19 mmol) in a 1:1:1 mixture oftetrahydrofuran:water:methanol (1.90 mL) at room temperature. Thereaction mixture was heated at 60° C. under microwave irradiation for 30mins. If necessary, additional portions of lithium hydroxide monohydratewere added, and subsequent heating under microwave irradiation wasperformed to drive the reaction to completion. The reaction mixture wasthen cooled to room temperature, quenched with a 1N aqueous solution ofHCl (1.0 mL) and concentrated to dryness. The crude residue was purifiedby flash column chromatography on C₁₈ reverse phase (water:acetonitrilegradient with 0.05% formic acid) to give2-((1r,4r)-4-(4-(2,2-dimethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid B-28 (36.0 mg, Yield=38% over 2 steps). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.13 (q, J=11.15 Hz, 2H), 1.34 (s, 6H), 1.49 (q, J=11.15 Hz, 2H),1.69-1.78 (m, 1H), 1.78-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.45-2.49(m, 1H), 3.64 (s, 2H), 7.00 (t, J=7.54 Hz, 1H), 7.12 (s, 1H), 7.16 (d,J=9.25 Hz, 1H), 7.26-7.31 (m, 4H), 7.47 (d, J=8.19 Hz, 1H), 7.50 (d,J=8.36 Hz, 2H), 7.55 (d, J=8.36 Hz, 2H), 9.24 (s, 1H), 12.25 (br s, 1H);MS (ESI) [M+1]⁺ 499.

Intermediate B-30: 6-bromoquinoxaline-2,3(1H,4H)-dione—step b15

4-Bromobenzene-1,2-diamine B-29 (232 mg, 1.24 mmol) and oxalic acid(135.0 mg, 1.24 mmol) were mixed as solids and were heated under vacuumat 160° C. for 8 h. The crude dark grey solid6-bromoquinoxaline-2,3(1H,4H)-dione B-30 (278.0 mg, ca. 1.12 mmol) wasused for next step without purification. MS (ESI) [M+1]⁺ 241, 243.

Intermediate B-31: 6-bromo-1,2,3,4-tetrahydroquinoxaline—step b16

Borane dimethyl sulfide complex (2 M solution in THF, 2.24 mL, 4.48mmol) was added at room temperature to a solution of6-bromoquinoxaline-2,3(1H,4H)-dione B-30 (278.0 mg, 1.12 mmol) inanhydrous THF (8.96 mL) under an argon atmosphere. The reaction mixturewas heated to reflux for 3.5 h, then cooled to room temperature,quenched slowly with methanol (2 mL) and concentrated to dryness underreduced pressure. The crude residue was purified by flash columnchromatography on silica gel (methylene chloride:ethyl acetate gradient)to give 6-bromo-1,2,3,4-tetrahydroquinoxaline B-31 as a light pink solid(181.2 mg, Yield=65% over 2 steps). MS (ESI) [M+1]⁺ 213, 215.

Intermediate B-32: methyl2-((1r,4r)-4-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate—stepb10

Intermediate B-32 was prepared by the procedure described for step b10,using 6-bromo-1,2,3,4-tetrahydroquinoxaline B-31 as starting material.MS (ESI) [M+1]⁺ 365.

Intermediates B-33 (mixture of regioisomers): methyl2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetateand methyl2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetate—stepb17

A solution of phenyl isocyanate (34.5 μL, 0.317 mmol) in anhydrousmethylene chloride (2.3 mL) was added at room temperature over 12 h(using a syringe pump) to a solution of methyl2-((1r,4r)-4-(4-(1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetateB-32 (105.0 mg, 0.288 mmol) in anhydrous methylene chloride (0.55 mL).After completion of the addition, the reaction mixture was stirred atroom temperature for 12 h, quenched with methanol (2.0 mL) andconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography on silica gel (90:10 to 0:100 gradient ofhexanes:ethyl acetate) to give a 1:1 mixture of the two regioisomersmethyl2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetateand methyl2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)acetateB-33 (139.8 mg, Yield=94%). MS (ESI) [M+1]⁺ 484.

Example B-34:2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)aceticacid—step b6

Example B-34 was prepared by the procedure described for step b6, usingthe 1:1 mixture of regioisomers B-33 as starting material. ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.77 Hz, 2H), 1.49 (q, J=11.77 Hz, 2H),1.69-1.78 (m, 1H), 1.83 (br d, J=9.62 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H),2.44-2.49 (m, 1H), 3.30 (br s, 2H), 3.68 (br s, 2H), 6.21 (br s, 1H),6.78 (d, J=8.51 Hz, 1H), 6.88 (s, 1H), 6.97 (t, J=7.25 Hz, 1H),7.20-7.30 (m, 4H), 7.47 (t, J=8.20 Hz, 3H), 8.79 (s, 1H), 12.13 (br s,1H); MS (ESI) [M+1]⁺ 470.

Example B-35:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)phenyl)cyclohexyl)aceticacid—step b6

Example B-35 was prepared by the procedure described for step b6, usingthe 1:1 mixture of regioisomers B-33 as starting material. ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.11 (q, J=12.20 Hz, 2H), 1.45 (q, J=12.20 Hz, 2H),1.68-1.76 (m, 1H), 1.80 (br t, J=11.03 Hz, 4H), 2.13 (d, J=6.62 Hz, 2H),2.39-2.47 (m, 1H), 3.30 (br s, 2H), 3.70 (t, J=4.70, 2H), 6.26 (br s,1H), 6.69 (d, J=8.51 Hz, 1H), 6.97 (t, J=7.25 Hz, 1H), 7.14 (dd, J=2.05,8.51 Hz, 1H), 7.20 (d, J=8.20, 2H), 7.26 (d, J=7.88 Hz, 2H), 7.39 (d,J=8.20 Hz, 2H), 7.44 (d, J=1.89 Hz, 1H), 7.50 (d, J=7.88 Hz, 2H), 8.85(s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 470.

Intermediate B-36: diethyl 2-(5-bromo-2-nitrophenoxy)malonate—step b18

5-Bromo-2-nitrophenol A-32 (0.40 g, 1.83 mmol) and diethyl2-bromomalonate (0.470 mL, 2.75 mmol) were mixed in anhydrous1-methylpyrrolidin-2-one (3.70 mL) under an atmosphere of argon at roomtemperature. Potassium fluoride (0.265 g, 4.58 mmol) was added, and thesolution was heated at 70° C. for 12 h. After cooling to roomtemperature, the reaction mixture was successively diluted with diethylether (25 mL), filtered, rinsed with diethyl ether (20 mL), quenchedwith water (25 mL) and decanted. The aqueous layer was extracted withdiethyl ether (2×50 mL). The combined organic extracts were successivelywashed with water (50 mL) and brine (50 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography onsilica gel (hexanes:ethyl acetate gradient) to give diethyl2-(5-bromo-2-nitrophenoxy)malonate B-36 as a yellow oil (553.0 mg,Yield=70%). MS (ESI) [M+1]⁺ 376, 378.

Intermediate B-37: ethyl7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate—step a24

Intermediate B-37 was prepared by the procedure described for step a24,using diethyl 2-(5-bromo-2-nitrophenoxy)malonate B-36 as startingmaterial. MS (ESI) [M+1]⁺ 300, 302.

Intermediate B-38:(7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol—step b16

Intermediate B-38 was prepared by the procedure described for step b16,using ethyl7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate B-37 asstarting material. MS (ESI) [M+1]⁺ 244, 246.

Intermediate B-39: methyl2-((1r,4r)-4-(4-(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb19

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (16.3 mg, 0.020 mmol), potassium carbonate (139.0mg, 1.0 mmol), 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanolB-38 (115.2 mg, 0.40 mmol) and methyl2-((1r,4r)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexyl)acetatetrans-A-5 (260.0 mg, 0.72 mmol) were mixed in a 4:1 mixture of1,4-dioxane:water (4.0 mL) at room temperature. The reaction mixture wasdegassed several times under reduced pressure and stirred for 12 h underan atmosphere of argon. The mixture was then filtered through a celitepad, washed with ethyl acetate (25 mL) and concentrated to dryness underreduced pressure. The residue was adsorbed on silica (5.0 g) andpurified by flash column chromatography on silica gel (hexanes:ethylacetate gradient) to give methyl2-((1r,4r)-4-(4-(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-39 as a light yellow solid (117.2 mg; Yield=67%). MS (ESI) [M+1]⁺ 396.

Intermediate B-40: methyl2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb20

Phenyl isocyanate (32.0 μL, 0.294 mmol) was added dropwise to a solutionof methyl2-((1r,4r)-4-(4-(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-39 (117.2 mg, 0.267 mmol) in methylene chloride (2.70 mL) at 0° C.under an atmosphere of argon. The reaction mixture was warmed slowly toroom temperature, stirred for 12 h, then quenched with methanol (1.0 mL)and concentrated to dryness under reduced pressure. The resulting purplesolid methyl2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-40 (141.6 mg, Yield=98%) was used as such for the next step withoutpurification. MS (ESI) [M+1]⁺ 515.

Example B-41:2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid—step b14

Intermediate B-41 was prepared by the procedure described for step b14,using methyl2-((1r,4r)-4-(4-(2-(hydroxymethyl)-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-40 as starting material. ¹H NMR (500 MHz, DMSO-d₆)

δ ppm 1.14 (q, J=12.13 Hz, 2H), 1.49 (q, J=12.13 Hz, 2H), 1.70-1.78 (m,1H), 1.83 (br d, J=10.56 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.49 (m,1H), 3.52 (dd, J=7.41, 13.24 Hz, 1H), 3.60 (dd, J=6.15, 11.19 Hz, 1H),3.70 (dd, J=4.89, 11.19 Hz, 1H), 4.13 (dd, J=2.36, 13.24 Hz, 1H),4.19-4.25 (m, 1H), 5.09 (br s, 1H), 7.00 (t, J=7.41 Hz, 1H), 7.15-7.18(m, 2H), 7.27-7.31 (m, 4H), 7.48-7.56 (m, 5H), 9.21 (s, 1H), 12.08 (brs, 1H); MS (ESI) [M+1]⁺ 501.

Intermediate B-42: methyl2-((1r,4r)-4-(4-(4-(chlorocarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb21

A solution of methyl2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-16 (1.6 g, 4.2 mmol) and dry pyridine (686 μL, 8.4 mmol) in anhydrousmethylene chloride (10.0 mL) was added dropwise to a solution oftriphosgene (504.0 mg, 1.66 mmol) in anhydrous methylene chloride (10.0mL) at −5° C. under an atmosphere of nitrogen. The reaction mixture waskept at −5° C. for 30 mins and was allowed to warm to room temperatureover 30 mins. It was then successively diluted with methylene chloride(25 mL), quenched with a 1 N aqueous solution of hydrogen chloride (1.0mL), diluted with water (10 mL) and decanted. The aqueous layer wasextracted with methylene chloride (3×30 mL). The combined organicextracts were washed with a 1 N aqueous solution of hydrogen chloride(20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filteredand concentrated to dryness under reduced pressure. The pink solidmethyl2-((1r,4r)-4-(4-(4-(chlorocarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-42 (1.74 g, Yield=94%) was used for the next step without purificationand stored at −20° C. under an atmosphere of nitrogen. MS (ESI) [M+1]⁺442.

Intermediate B-43: methyl2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetate—stepb22

A solution of methyl2-((1r,4r)-4-(4-(4-(chlorocarbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-42 (186.0 mg, 0.42 mmol) in anhydrous methylene chloride (2.0 mL) wasadded dropwise to a solution of 3-phenylpropan-1-amine (85.2 mg, 0.63mmol) and N-ethyl-N,N-diisopropylamine (104.0 μL, 0.63 mmol) inanhydrous methylene chloride (2.0 mL) at room temperature under anatmosphere of nitrogen. The reaction mixture was stirred for 16 h, thensequentially diluted with methylene chloride, washed with a 1 N aqueoussolution of hydrogen chloride (5.0 mL) and brine (25 mL), dried overanhydrous sodium sulfate, filtered and concentrated to dryness underreduced pressure. The crude residue (225.0 mg) was purified by flashcolumn chromatography on silica gel (hexanes:ethyl acetate gradient) togive methyl2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-43 (181.0 mg, Yield=80%) as a light pink solid. MS (ESI) [M+1]⁺ 541.

Example B-44:2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid—step b14

Intermediate B-44 was prepared by the procedure described for step b14,using methyl2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetateB-43 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (dq,J=12.50, 2.00 Hz, 2H), 1.31 (d, J=6.50 Hz, 3H), 1.49 (dq, J=12.50, 2.00Hz, 2H),1.69-1.88 (m, 7H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 1H),2.62 (t, J=7.72 Hz, 2H), 3.22 (dd, J=13.50, 8.00 Hz, 1H), 3.97 (dd,J=13.50, 1.75 Hz, 1H), 4.20-4.30 (m, 1H), 7.00 (t, J=5.20 Hz, 1H), 7.10(d, J=1.50 Hz, 1H), 7.13 (dd, J=8.50, 2.00 Hz, 1H), 7.18 (t, J=7.25 Hz,1H), 7.23 (d, J=7.00 Hz, 2H), 7.25-7.31 (m, 4H), 7.53 (d, J=7.88 Hz,2H), 7.61 (d, J=8.51 Hz, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺ 527.

Intermediate B-46:7-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)quinoline-4-carboxylicacid—step b2

Intermediate B-46 was prepared by the procedure described for step b2,using 7-bromoquinoline-4-carboxylic acid B-45 as starting material. MS(ESI), [M+1]⁺ 404.

Intermediate B-47: methyl2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetate—stepb23

N-Ethyl-N,N-diisopropylamine (64.5 mg, 0.50 mmol) was added at roomtemperature to a solution of aniline (465.0 mg, 0.50 mmol),7-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)quinoline-4-carboxylicacid B-46 (101.0 mg, 0.25 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (190.0 mg, 0.50 mmol) in anhydrousN,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. Thereaction mixture was stirred overnight, then partitioned betweenmethylene chloride (30 mL) and an aqueous solution of pH 7 phosphatebuffer (30 mL). The aqueous layer was extracted with methylene chloride(3×30 mL); the combined extracts were successively washed with water (30mL), brine (30 mL), then dried over anhydrous magnesium sulfate,filtered and concentrated to dryness under reduced pressure. The cruderesidue was purified by flash column chromatography on silica gel(hexanes:ethyl acetate gradient) to give methyl2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetateB-47 (107.0 mg, Yield=90%). MS (ESI), [M+1]⁺ 479.

Example B-48:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid—step b24

A 1 N aqueous solution of sodium hydroxide (3.0 mL) was added to asolution of methyl2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)acetateB-47 (94.0 mg, 0.20 mmol) in a 1:5 mixture of tetrahydrofuran: methanol(10.0 mL) at room temperature. After 12 h of vigorous stirring, theaqueous layer was then acidified to pH 1 using a 1 N aqueous solution ofhydrogen chloride. The resulting solution was concentrated to drynessunder reduced pressure. The crude residue was purified by flash columnchromatography on C₁₈ reverse phase (water:acetonitrile gradient with0.05% formic acid) to give2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid B-48 (65.2 mg, Yield=70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q,J=11.5 Hz, 2H), 1.53 (q, J=11.5 Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d,J=7.0 Hz, 2H), 2.48-2.54 (m, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.41-7.43 (m,3H), 7.73 (d, J=8.0 Hz, 1H), 7.82 (d, J=9.0 Hz, 5H), 8.05 (d, J=9.0 Hz,1H), 8.23 (d, J=9.0 Hz, 1H), 8.36 (s, 1H), 9.08 (d, J=9.0 Hz, 1H), 10.82(s, 1H); MS (ESI) [M+1]⁺ 465.

Intermediate B-50: tert-butyl5-(phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate—step b25

Aniline (118.3 μL, 1.082 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (616.9 mg, 1.622 mmol) andN-ethyl-N,N-diisopropylamine (565.3 μL, 3.245 mmol) were successivelyadded at room temperature to a solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acidB-49 (300.0 mg, 1.082 mmol) in methylene chloride (10.0 mL). Thereaction mixture was stirred at room temperature for 12 h, thenconcentrated to dryness under reduced pressure and purified by flashcolumn chromatography on silica gel (hexanes:ethyl acetate gradient) togive tert-butyl5-(phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate B-50 as awhite solid (374.9 mg, Yield=98%). ¹H NMR (500 MHz, CHLOROFORM-d₃) δ ppm1.51 (s, 9H), 3.09 (t, J=5.50 Hz, 2H), 3.62-3.67 (m, 2H), 4.64 (s, 2H),7.19 (t, J=7.50 Hz, 1H), 7.25-7.31 (m, 2H), 7.39-7.43 (m, 3H), 4.64 (brs, 1H), 7.64 (d, J=7.50 Hz, 2H).

Intermediate B-51:N-phenyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide—step b26

tert-butyl 5-(phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateB-50 (374.9 mg, 1.352 mmol) was dissolved in a 4 N solution of hydrogenchloride in dioxane (10.0 mL) and stirred at room temperature under anatmosphere of nitrogen for 3 h. The reaction mixture was thenconcentrated to dryness under reduced pressure to give crudeN-phenyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide B-51 (248.7 mg,Yield=81%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.10-3.13 (m, 2H), 3.34-3.37(m, 2H), 4.33 (s, 2H), 7.10 (t, J=7.50 Hz, 1H), 7.33-7.41 (m, 3H), 7.50(d, J=7.50 Hz, 1H), 7.74 (d, J=7.50 Hz, 2H), 9.37 (br s, 2H), 10.43 (s,1H).

Example B-52: methyl2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetate—stepb27

Palladium (II) acetate (2.90 mg, 0.013 mmol), cesium carbonate (256.9mg, 0.789 mmol), methyl2-((1r,4r)-4-(4-(trifluoromethylsulfonyloxy)phenyl)-cyclohexyl)acetateA-4 (100.0 mg, 0.263 mmol),(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (13.1 mg, 0.021 mmol)and N-phenyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide B-51 (113.9mg, 0.394 mmol) were mixed in anhydrous toluene (5.0 mL) in a sealedtube. The reaction mixture was degassed several times under reducedpressure, heated at 120° C. and stirred for 15 h. The mixture was thenfiltered through a celite pad, washed with ethyl acetate (30 mL) andconcentrated to dryness under reduced pressure. The residue was adsorbedon silica (1.0 g) and purified by flash column chromatography on silicagel (hexanes:ethyl acetate gradient) to give methyl2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetateB-52 as a yellow solid (38.5 mg; Yield=79%). ¹H NMR (500 MHz, CDCl₃) δppm 1.13-1.21 (m, 2H), 1.46-1.54 (m, 2H), 1.84-1.96 (m, 5H), 2.28 (d,J=6.50 Hz, 2H), 2.41-2.46 (m, 1H), 3.24 (t, J=6.00 Hz, 2H), 3.53 (d,J=6.00 Hz, 2H), 3.71 (s, 3H), 4.44 (s, 2H), 6.96 (d, J=8.50 Hz, 2H),7.15-7.20 (m, 3H), 7.29-7.30 (m, 2H), 7.39-7.44 (m, 3H), 7.50 (br s,1H), 7.65 (d, J=7.50 Hz, 2H); MS (ESI) [M+1]⁺ 483.

Example B-53:2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)aceticacid—step b3

Example B-53 was prepared by the procedure described for step b3, usingmethyl2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)cyclohexyl)acetateB-52 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.06-1.14 (m,2H), 1.37-1.45 (m, 2H), 1.69-1.81 (m, 5H), 2.14 (d, J=7.00 Hz, 2H),2.33-2.38 (m, 1H), 3.00 (t, J=5.50 Hz, 2H), 3.49 (t, J=5.50 Hz, 2H),4.41 (s, 2H), 6.94-6.96 (m, 2H), 7.09-7.11 (m, 3H), 7.31-7.37 (m, 5H),7.75 (d, J=8.00 Hz, 2H), 10.33 (s, 1H), 12.04 (br s, 1H); MS (ESI)[M+1]⁺ 469.

Intermediate B-55: methyl2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate—stepb9

Intermediate B-55 was prepared by the procedure described for step b9,using tert-butyl7-(4-((1r,4r)-4-(2-methoxy-2-oxoethyl)cyclohexyl)phenyl)-1-(phenylcarbamoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylateB-54 as starting material. MS (ESI) [M+1]⁺ 498.

Intermediate B-56: methyl2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetate—stepb28

Sodium cyanoborohydride (40.0 mg, 0.60 mmol) was added at 0° C. to asolution of methyl2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetateB-55 (99.4 mg, 0.20 mmol) and formaldehyde (20.0 mg, 0.60 mmol) inanhydrous acetonitrile (5.0 mL) under an atmosphere of argon. Thereaction mixture was allowed to warm to room temperature, then stirredfor 15 mins and treated with acetic acid (47 μL, 0.80 mmol). Thereaction mixture was stirred at room temperature for 12 h and thentreated with a 10% solution of potassium carbonate (3.0 mL) anddecanted. The aqueous layer was extracted with methylene chloride (3×30mL). The combined organic extracts were washed with brine (20 mL), driedover anhydrous magnesium sulfate, filtered and concentrated to drynessunder reduced pressure. The crude methyl2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetateB-56 was used for the next step without purification. MS (ESI) [M+1]⁺512.

Example B-57:2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)aceticacid—step b24

Example B-57 was prepared by the procedure described for step b24, usingmethyl2-((1r,4r)-4-(4-(4-methyl-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)acetateB-56 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q,J=12.0 Hz, 2H), 1.53 (q, J=12.0 Hz, 2H), 1.75-1.86 (m, 5H), 2.17 (d,J=7.0 Hz, 2H), 2.26 (s, 3H), 2.54 (m, 1H), 3.45-3.56 (m, 4H), 4.56 (s,2H), 6.98 (t, J=7.5 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.5 Hz,2H), 7.42-7.45 (m, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H),7.94 (s, 1H), 8.49 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 498.

Section C Example Compounds Preparation of Examples C-1 to C-157

The following examples were prepared using the general proceduresoutlined in section B, using reagents from commercial sources orintermediates either prepared with procedures outlined in section A orsection B or published literature procedures.

Example C-1:2-((1r,4r)-4-(4-(1-(4-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.98 Hz, 2H), 1.49 (q,J=11.98 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.60 Hz,2H), 2.46-2.48 (m, 1H), 3.24 (t, J=8.50 Hz, 2H), 4.16 (t, J=8.50 Hz,2H), 7.15 (t, J=8.83 Hz, 2H), 7.28 (d, J=8.20 Hz, 2H), 7.42 (d, J=8.51Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=8.20 Hz, 2H), 7.56-7.61 (m, 2H), 7.91(d, J=8.20 Hz, 1H), 8.61 (s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]⁺ 473.

Example C-2:2-((1r,4r)-4-(4-(1-(3-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.55 Hz, 2H), 1.49 (q,J=11.55 Hz, 2H), 1.75 (br s, 1H), 1.79-1.87 (m, 4H), 2.15 (d, J=6.62 Hz,2 H), 2.45-2.48 (m, 1H), 3.26 (t, J=8.20 Hz, 2H), 4.20 (t, J=8.20 Hz,2H), 7.29 (d, J=8.20 Hz, 2H), 7.36 (d, J=8.80 Hz, 1H), 7.44 (d, J=8.51Hz, 1H), 7.51 (s, 1H), 7.52-7.57 (m, 3H), 7.90 (d, J=8.20 Hz, 1H), 7.93(d, J=8.20 Hz, 1H), 8.05 (s, 1H), 8.88 (s, 1H), 12.10 (br s, 1H); MS(ESI) [M+1]⁺ 523.

Example C-3:2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.85 Hz, 2H), 1.52 (q,J=12.00 Hz, 2H), 1.70 (br s, 1H), 1.75-1.80 (m, 4H), 2.19 (d, J=6.62 Hz,2 H), 2.52-2.55 (m, 1H), 6.81 (d, J=3.00 Hz, 1H), 7.16 (t, J=7.50 Hz,1H), 7.21-7.49 (m, 4H), 7.50-7.74 (m, 5H), 7.89 (s, 1H), 8.07 (d, J=3.50Hz, 1H), 8.28 (d, J=8.00 Hz, 1H), 10.10 (s, 1H); MS (ESI) [M+1]⁺ 453.

Example C-4:2-((1r,4r)-4-(4-(1-(pyridin-3-ylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.09 (q, J=11.75 Hz, 2H), 1.53 (q,J=11.75 Hz, 2H), 1.75 (br s, 1H), 1.75-1.82 (m, 4H), 2.18 (d, J=6.94 Hz,2H), 2.50-2.55 (m, 1H), 7.02 (m, 1H), 7.28-7.37 (m, 4H), 7.45 (d, J=8.51Hz, 1H), 7.62 (d, J=7.25 Hz, 2H), 7.68 (s, 1H), 7.79 (d, J=8.20 Hz, 2H),8.24 (d, J=8.51 Hz, 1H), 8.33 (br s, 1H), 9.76 (s, 1H), 11.81 (br s,1H); MS (ESI) [M+1]⁺ 454.

Example C-5:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.40 Hz, 2H), 1.49 (q,J=11.40 Hz, 2H), 1.70-1.86 (m, 5H), 2.16 (d, J=6.94 Hz, 2H), 2.52-2.55(m, 1H), 3.85 (t, J=4.10 Hz, 2H), 4.25 (t, J=4.10 Hz, 2H), 7.01 (t,J=7.25 Hz, 1H), 7.11-7.20 (m, 2H), 7.26-7.29 (m, 4H), 7.45-7.60 (m, 5H),9.17 (s, 1H), 12.05 (s, 1H); MS (ESI) [M+1]⁺ 471.

Example C-6:2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.35 Hz, 2H), 1.48 (q,J=11.35 Hz, 2H), 1.69-1.78 (m, 1H), 1.78-1.88 (m, 4H), 2.15 (d, J=6.62Hz, 2H), 2.49 (br s, 1H), 3.85 (t, J=4.10 Hz, 2H), 4.25 (t, J=4.10 Hz,2H), 6.65 (d, J=8.20 Hz, 1H), 6.92-7.07 (m, 2H), 7.17-7.35 (m, 3H), 7.43(d, J=7.88 Hz, 2H), 7.47-7.62 (m, 2H), 9.00 (s, 1H); MS (ESI) [M+1]⁺557.

Example C-7:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.40 Hz, 2H), 1.52 (q,J=11.40 Hz, 2H), 1.75-1.85 (m, 5H), 2.16 (d, J=6.94 Hz, 2H), 2.53-2.56(m, 1H), 3.85 (t, J=4.10 Hz, 2H), 4.27 (t, J=4.10 Hz, 2H), 6.90-7.03 (m,3H), 7.24-7.32 (m, 4H), 7.38-7.51 (m, 5H), 9.15 (s, 1H); MS (ESI) [M+1]⁺471.

Example C-8:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.42 Hz, 2H), 1.50 (q,J=11.38 Hz, 2H), 1.73-1.85 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.52-2.55(m, 1H), 3.87 (t, J=4.10 Hz, 2H), 4.28 (t, J=4.10 Hz, 2H), 6.94-7.03 (m,3H), 7.21-7.33 (m, 4H), 7.39-7.48 (m, 3H), 7.52 (d, J=8.20 Hz, 1H),7.77-7.79 (m, 1H), 9.22 (s, 1H); MS (ESI) [M+1]⁺ 471.

Example C-9:2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.08 (q, J=11.54 Hz, 2H), 1.57 (q,J=11.60 Hz, 2H), 1.70-1.93 (m, 5H), 1.82-1.99 (m, 2H), 2.04-2.30 (m,2H), 2.52-2.56 (m, 1H), 2.71-2.86 (m, 2H), 3.59-3.79 (m, 2H), 6.55 (s,1H), 6.91-7.14 (m, 1H), 7.29 (s, 4H), 7.39-7.40 (m, 2H), 7.45-7.65 (m,4H), 8.95 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]⁺ 469.

Example C-10:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.42 Hz, 2H), 1.52 (q,J=11.58 Hz, 2H), 1.73-1.82 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.51-2.55(m, 1H), 4.10 (t, J=4.00 Hz, 2H), 4.34 (t, J=4.00 Hz, 2H), 7.06-7.10 (m,1H), 7.35-7.38 (m, 4H) 7.59-7.70 (m, 4H), 7.72-7.78 (m, 1H), 8.42 (s,1H), 12.05 (br s, 1H), 12.88 (s, 1H); MS (ESI) [M+1]⁺ 472.

Example C-11:2-((1s,4s)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (q, J=11.40 Hz, 2H), 1.50 (q,J=11.35 Hz, 2H), 1.58-1.66 (m, 4H), 1.75-1.82 (m, 1H), 2.38 (d, J=6.94Hz, 2H), 2.50-2.55 (m, 1H), 3.87 (t, J=4.10 Hz, 2H), 4.30 (t, J=4.10 Hz,2H), 7.01 (t, J=7.25 Hz, 1H), 7.11-7.20 (m, 2H) 7.27-7.34 (m, 4H),7.45-7.60 (m, 5H), 9.16 (s, 1H); MS (ESI) [M+1]⁺ 471.

Example C-12:2-(4-(4-(1-(phenylcarbamoyl)indolin-5-yl)phenyl)piperazin-1-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.53 (s, 2H), 3.58-3.62 (m, 2H),3.80-4.20 (m, 6H), 7.02-7.09 (m, 3H), 7.36 (m, 2H), 7.40-7.47 (m, 1H),7.50 (m, 1H), 7.47-7.63 (m, 4H), 7.93-7.98 (m, 1H), 8.56-8.60 (m, 1H),10.5 (s, 1H); MS (ESI) [M+1]⁺ 457.

Example C-13:(1R,2S)-2-(4-(1-(phenylcarbamoyl)indolin-5-yl)benzoyl)cyclopentanecarboxylicacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.55-1.70 (m, 2H), 1.70-1.87 (m, 2H),1.98-2.06 (m, 1H), 2.13-2.22 (m, 1H), 3.22 (m, 2H), 4.04-4.12 (m, 1H),4.20 (t, J=8.51 Hz, 2H), 7.04 (t, J=7.25 Hz, 1H), 7.31 (t, J=7.41 Hz,2H), 7.58 (d, J=8.20 Hz, 3H), 7.64 (s, 1H), 7.82 (d, J=7.57 Hz, 2H),7.97 (d, J=8.51 Hz, 1H), 8.06 (d, J=7.88 Hz, 2H), 8.61 (s, 1H); MS (ESI)[M+1]⁺ 455.

Example C-14:2-((1r,4r)-4-(4-(5-(phenylcarbamoyl)naphthalen-2-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.60 Hz, 2H), 1.53 (q,J=11.58 Hz, 2H), 1.73-1.80 (m, 5H), 2.19 (d, J=7.25 Hz, 2H), 2.54 (m,1H), 7.12-7.18 (m, 1H), 7.36-7.54 (m, 4H), 7.59-7.70 (m, 4H), 7.74-7.90(m, 3H), 8.13-8.39 (m, 3H), 10.61 (s, 2H), 12.05 (br s, 1H); MS (ESI)[M+1]⁺ 464.

Example C-15:2-((1r,4r)-4-(4-(4-(benzo[d]oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.35 Hz, 2H), 1.70-1.95 (m, 5H), 2.19 (d, J=7.25 Hz, 2H), 2.53 (m,1H), 4.22 (t, J=4.10 Hz, 2H), 4.44 (t, J=4.10 Hz, 2H), 7.10-7.33 (m,5H), 7.46-7.62 (m, 4H), 8.38-8.54 (m, 2H); MS (ESI) [M+1]⁺ 469.

Example C-16:2-((1r,4r)-4-(4-(2-(phenylamino)quinazolin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.42 Hz, 2H), 1.54 (q,J=11.40 Hz, 2H), 1.80-1.87 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.53 (m,1H), 7.00 (t, J=7.25 Hz, 1H), 7.29-7.41 (m, 5H), 7.68-7.76 (m, 3H), 8.00(d, J=8.20 Hz, 2H), 8.15 (d, J=8.83 Hz, 1H), 8.20 (s, 1H), 9.36 (s, 1H),9.93 (s, 1H); MS (ESI) [M+1]⁺ 438.

Example C-17:2-((1r,4r)-4-(4-(2-(phenylamino)benzo[d]oxazol-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (q, J=11.62 Hz, 2H), 1.56 (q,J=11.50 Hz, 2H), 1.68-1.72 (m, 5H), 2.16 (d, J=6.62 Hz, 2H), 2.55 (m, 1H), 3.59 (br s, 1H), 6.63 (s, 1H), 7.05 (t, J=7.09 Hz, 1H), 7.32 (d,J=7.57 Hz, 2H), 7.39 (t, J=7.57 Hz, 2H), 7.46-7.57 (m, 2H), 7.62 (d,J=7.88 Hz, 2H), 7.78 (d, J=6.62 Hz, 2H), 10.70 (s, 1H); MS (ESI) [M+1]⁺427.

Example C-18:2-((1r,4r)-4-(4-(3-(phenylcarbamoyl)-1H-indol-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.15-1.19 (q, J=11.35 Hz, 2H), 1.53(q, J=11.35 Hz, 2H), 1.85-1.95 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.53(m, 1H), 7.12-7.18 (m, 1H), 7.30-7.40 (m, 4H), 7.50-7.70 (m, 5H), 7.91(s, 1H), 7.95 (s, 1H), 8.00-8.20 (m, 3H); MS (ESI) [M+1]⁺ 453.

Example C-19:2-((1r,4r)-4-(4-(2-(phenylcarbamoyl)-1H-benzo[d]imidazol-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (q, J=11.44 Hz, 2H), 1.46 (q,J=11.50 Hz, 2H), 1.83-1.85 (m, 5H), 2.16 (d, J=6.31 Hz, 2H), 2.51 (m,1H), 6.94-7.14 (m, 1H), 7.28-7.40 (m, 5H), 7.43 (s, 1H), 7.47-7.57 (m,4H), 8.18 (d, J=7.88 Hz, 1H), 9.45 (s, 1H), 12.26-12.64 (m, 1H); MS(ESI) [M+1]⁺ 454.

Example C-20:(1S,2S)-2-(4-(1-(phenylcarbamoyl)-1H-indol-5-yl)benzoyl)cyclopentanecarboxylicacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.55-1.70 (m, 2H), 1.70-1.87 (m, 2H),1.98-2.06 (m, 1H), 2.13-2.22 (m, 1H), 3.22-3.40 (m, 2H), 6.86 (d, J=3.50Hz, 1H), 7.16 (t, J=7.25 Hz, 1H), 7.41 (t, J=7.41 Hz, 2H), 7.68 (d,J=8.50 Hz, 2H), 7.73 (s, 1H), 7.92 (d, J=7.57 Hz, 2H), 8.05 (s, 1H),8.10-8.16 (m, 3H), 8.33 (d, J=8.00 Hz, 1H), 10.14 (s, 1H); MS (ESI)[M+1]⁺ 453.

Example C-21:2-((1r,4r)-4-(4-(4-(2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.47 (q,J=11.50 Hz, 2H), 1.72-1.80 (m, 5H), 2.15 (d, J=6.62 Hz, 2H), 2.53 (m,1H), 3.32 (t, J=4.00 Hz, 2H), 4.15 (t, J=4.00 Hz, 2H), 6.65 (d, J=8.20Hz, 1H), 6.94 (br s, 1H), 6.98-7.07 (m, 1H), 7.22 (d, J=8.00 Hz, 2H),7.25-7.35 (m, 1H), 7.43 (d, J=7.88 Hz, 2H) 7.47-7.62 (m, 2H), 8.30 (s,1H), 9.00 (s, 1H); MS (ESI) [M+1]⁺ 539.

Example C-22:2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-1H-indazol-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.50 Hz, 2H), 1.53 (q,J=11.50 Hz, 2H), 1.73-1.86 (m, 5H), 2.17 (d, J=6.94 Hz, 2H), 2.53 (m,1H), 7.15 (t, J=7.50 Hz, 1H), 7.32-7.42 (m, 5H), 7.67 (d, J=7.88 Hz,2H), 7.82 (d, J=8.20 Hz, 2H), 7.92 (d, J=9.50 Hz, 1H), 8.15 (s, 1H),8.39 (d, J=5.00 Hz, 1H), 8.55 (s, 1H); MS (ESI) [M+1]⁺ 454.

Example C-23:2-((1r,4r)-4-(4-(4-(4-ethoxyphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.19 (t,J=7.80 Hz, 3H), 1.49 (q, J=11.50 Hz, 2H), 1.72-1.85 (m, 5H), 2.17 (d,J=6.62 Hz, 2H), 2.53 (m, 1H), 3.85 (t, J=4.00 Hz, 2H), 3.96 (q, J=7.80Hz, 2H), 4.29 (t, J=4.00 Hz, 2H), 6.83-6.87 (m, 2H), 7.15-7.16 (m, 2H),7.28-7.33 (m, 2H), 7.38 (d, J=9.00 Hz, 2H), 7.54 (d, J=8.00 Hz, 2H),7.57-7.59 (m, 1H), 8.99 (s, 1H); MS (ESI) [M+1]⁺ 515.

Example C-24:2-((1r,4r)-4-(4-(4-(4-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.50 Hz, 2H), 1.49 (q,J=11.50 Hz, 2H), 172-1.84 (m, 5H), 2.14 (d, J=6.00 Hz, 2H), 2.53 (m,1H), 3.88 (t, J=4.00 Hz, 2H), 4.31 (t, J=4.00 Hz, 2H), 7.15-7.18 (m,2H), 7.29 (d, J=7.50 Hz, 2H), 7.55 (d, J=13.50 Hz, 2H), 7.57 (d, J=9.00Hz, 1H), 7.63-7.73 (m, 4H), 8.44 (s, 1H), 9.58 (s, 1H); MS (ESI) [M+1]⁺539.

Example C-25:2-((1r,4r)-4-(4-(4-(perfluorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.47 (q,J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m,1H), 3.93 (t, J=4.00 Hz, 2H), 4.33 (t, J=4.00 Hz, 2H), 7.17-7.19 (m,2H), 7.29 (d, J=8.50 Hz, 2H), 7.54 (d, J=8.00 Hz, 2H), 7.68 (d, J=9.00Hz, 1H), 9.29 (s, 1H); MS (ESI) [M+1]⁺ 561.

Example C-26:2-((1r,4r)-4-(4-(4-(2-cyanophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.46 (q,J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m,1H), 3.93 (t, J=4.00 Hz, 2H), 4.22 (t, J=4.00 Hz, 2H), 7.18-7.20 (m,3H), 7.28-7.34 (m, 3H), 7.54-7.58 (m, 3H), 7.68 (d, J=9.00 Hz, 1H), 7.80(d, J=8.50 Hz, 1H), 9.46 (s, 1H); MS (ESI) [M+1]⁺ 496.

Example C-27:2-((1r,4r)-4-(4-(4-(2-nitrophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.47 (q,J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m,1H), 3.89 (t, J=4.00 Hz, 2H), 4.33 (t, J=4.00 Hz, 2H), 7.20 (s, 1H)7.26-7.33 (m, 2H), 7.56 (d, J=7.57 Hz, 2H), 7.64-7.73 (m, 3H), 7.77 (d,J=8.50 Hz, 2H), 7.99 (d, J=8.20 Hz, 1H), 9.93 (s, 1H); MS (ESI) [M+1]⁺496.

Example C-28:2-((1r,4r)-4-(4-(4-(4-(cyanomethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.20 (q, J=11.80 Hz, 2H), 1.58 (q,J=11.80 Hz, 2H), 1.91-2.00 (m, 5H), 2.35 (d, J=7.00 Hz, 2H), 2.56 (m,1H), 3.75 (s, 2H), 4.01 (t, J=5.50 Hz, 2H), 4.38 (t, J=5.50 Hz, 2H),7.20-7.24 (m, 2H), 7.21-7.33 (m, 4H), 7.38 (d, J=8.00 Hz, 1H), 7.47 (d,J=8.51 Hz, 2H), 7.53 (d, J=7.88 Hz, 2H), 8.05 (s, 1H); MS (ESI) [M+1]⁺510.

Example C-29:2-((1r,4r)-4-(4-(4-(2-(methoxycarbonyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.20 (q, J=11.80 Hz, 2H), 1.57 (q,J=11.80 Hz, 2H), 1.94-2.09 (m, 5H), 2.35 (d, J=6.94 Hz, 2H), 2.56 (m,1H), 3.83 (s, 3H), 4.00 (t, J=4.50 Hz, 2H), 4.39 (t, J=4.50 Hz, 2H),7.06 (q, J=7.15 Hz, 1H), 7.19-7.25 (m, 2H), 7.26-7.33 (m, 2H), 7.56 (d,J=7.88 Hz, 1H), 7.64 (d, J=8.20 Hz, 1H), 8.06 (d, J=7.25 Hz, 1H), 8.02(d, J=8.20 Hz, 1H), 8.57 (d, J=8.51 Hz, 1H), 8.55 (d, J=8.51 Hz, 1H),10.84 (br s, 1H), 10.98 (s, 1H); MS (ESI) [M+1]⁺ 529.

Example C-30:2-((1r,4r)-4-(4-(4-(2-fluoro-5-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.51 (q,J=11.50 Hz, 2H), 1.71-1.84 (m, 5H), 2.15 (d, J=6.00 Hz, 2H), 2.53 (m,1H), 3.90 (t, J=4.50 Hz, 2H), 4.32 (t, J=4.50 Hz, 2H), 7.15-7.23 (m,1H), 7.30 (d, J=8.20 Hz, 1H), 7.42-7.57 (m, 4H), 7.64-7.70 (m, 1H), 8.03(d, J=5.67 Hz, 1H), 8.63 (d, J=5.67 Hz, 1H), 9.15 (s, 1H), 9.48-9.53 (m,1H), 12.05 (s, 1H); MS (ESI) [M+1]⁺ 557.

Example C-31:2-((1r,4r)-4-(4-(4-(2-chloro-6-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.50 Hz, 2H), 1.49 (q,J=11.50 Hz, 2H), 1.70-1.84 (m, 5H), 2.15 (d, J=6.00 Hz, 2H), 2.51 (m,1H), 3.82 (t, J=4.50 Hz, 2H), 4.39 (t, J=4.50 Hz, 2H), 7.17-7.22 (m,4H), 7.29 (d, J=8.00 Hz, 1H), 7.53-7.59 (m, 2H), 7.63 (d, J=8.00 Hz,1H), 7.78 (d, J=8.00 Hz, 1H), 7.92 (d, J=8.00 Hz, 1H), 9.00 (s, 1H); MS(ESI) [M+1]⁺ 574.

Example C-32:2-((1r,4r)-4-(4-(4-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.49 (q,J=11.50 Hz, 2H), 1.71-1.84 (m, 5H), 2.14 (d, J=6.00 Hz, 2H), 2.49 (m,1H), 3.91 (t, J=4.50 Hz, 2H), 4.30 (t, J=4.50 Hz, 2H), 7.17-7.18 (m,4H), 7.29 (d, J=8.50 Hz, 1H), 7.58-7.69 (m, 4H), 7.55 (d, J=8.00 Hz,1H), 8.84 (s, 1H); MS (ESI) [M+1]⁺ 557.

Example C-33:2-((1r,4r)-4-(4-(1-(3-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.35 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.94 Hz,2H), 2.30 (s, 3H), 2.44-2.48 (m, 1H), 3.23 (t, J=8.51 Hz, 2H), 4.16 (t,J=8.51 Hz, 2H), 6.84 (d, J=7.57 Hz, 1H), 7.18 (t, J=7.57 Hz, 1H), 7.28(d, J=7.88 Hz, 2H), 7.37 (d, J=8.20 Hz, 1H), 7.40-7.44 (m, 2H), 7.49 (s,1H), 7.53 (d, J=7.88 Hz, 2H), 7.91 (d, J=8.20 Hz, 1H), 8.48 (s, 1H),12.23 (br s, 1H); MS (ESI) [M+1]⁺ 469.

Example C-34:2-((1r,4r)-4-(4-(1-(3-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.30 Hz, 2H), 1.75 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.94 Hz,2H), 2.44-2.49 (m, 1H), 3.24 (t, J=8.60 Hz, 2H), 4.18 (t, J=8.60 Hz,2H), 6.84 (t, J=8.00 Hz, 1H), 7.29 (d, J=8.10 Hz, 2H), 7.33 (br q,J=8.00 Hz, 1H), 7.40 (d, J=8.40 Hz, 1H), 7.44 (d, J=8.40 Hz, 1H), 7.50(s, 1H), 7.54 (d, J=8.20 Hz, 2H), 7.56 (d, J=9.50 Hz, 1H), 7.92 (d,J=8.51 Hz, 1H), 8.75 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]⁺ 473.

Example C-35:2-((1r,4r)-4-(4-(1-(2-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.35 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.62 Hz,2H), 2.25 (s, 3H), 2.44-2.48 (m, 1H), 3.26 (t, J=8.51 Hz, 2H), 4.17 (t,J=8.51 Hz, 2H), 7.12 (t, J=7.40 Hz, 1H), 7.20 (t, J=7.57 Hz, 1H), 7.25(d, J=7.57 Hz, 1H), 7.28 (d, J=8.10 Hz, 2H), 7.33 (d, J=7.88 Hz, 1H),7.40 (d, J=8.51 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=8.10 Hz, 2H), 7.87 (d,J=8.51 Hz, 1H), 8.16 (s, 1H), 12.13 (br s, 1H); MS (ESI) [M+1]⁺ 469.

Example C-36:2-((1r,4r)-4-(4-(4-(3,5-bis(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11 (q, J=11.50 Hz, 2H), 1.48 (q,J=11.50 Hz, 2H), 1.71-1.84 (m, 5H), 2.14 (d, J=6.00 Hz, 2H), 2.49 (m,1H), 3.91 (t, J=4.50 Hz, 2H), 4.33 (t, J=4.50 Hz, 2H), 7.17-7.18 (m,4H), 7.30 (d, J=8.50 Hz, 1H), 7.56 (d, J=8.00 Hz, 1H), 7.63 (d, J=8.00Hz, 1H), 7.69 (s, 1H); 8.24 (s, 2H); 9.81 (s, 1H); MS (ESI) [M+1]⁺ 607.

Example C-37:2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.09-1.20 (m, 5H), 1.50 (q, J=11.50 Hz,2H), 1.71-1.83 (m, 5H), 2.15 (d, J=6.00 Hz, 2H), 2.49 (m, 1H), 2.60 (q,J=7.50 Hz, 2H), 3.90 (t, J=4.50 Hz, 2H), 4.32 (t, J=4.50 Hz, 2H),7.14-7.20 (m, 4H), 7.22-7.33 (m, 4H), 7.54 (d, J=8.00 Hz, 1H), 7.71 (d,J=8.00 Hz, 1H), 8.56 (s, 2H), 12.05 (s, 1H); MS (ESI) [M+1]⁺ 499.

Example C-38:2-((1r,4r)-4-(4-(1-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (q, J=11.50 Hz, 2H), 1.49 (q,J=11.50 Hz, 2H), 1.72-1.84 (m, 5H), 1.94 (t, J=7.50 Hz, 2H), 2.15 (d,J=6.50 Hz, 2H), 2.53 (m, 1H), 2.84 (t, J=7.50 Hz, 2H), 3.77 (t, J=7.50Hz, 2H), 7.18-7.36 (m, 2H), 7.41-7.67 (m, 7H), 8.02 (d, J=5.50 Hz, 1H),8.88 (s, 1H), 12.05 (s, 1H); MS (ESI) [M+1]⁺ 555.

Example C-39:2-((1r,4r)-4-(4-(1-(cyclohexylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 1.17-1.46 (m, 7H), 1.53-1.65 (m,2H), 1.69 (br d, J=12.9 Hz, 1H), 1.77-1.91 (m, 3H), 1.91-2.02 (m, 6H),2.25 (d, J=6.94 Hz, 2H), 2.53 (br s, 1H), 3.24 (t, J=8.51 Hz, 2H),3.63-3.70 (m, 1H), 3.97 (t, J=8.51 Hz, 2H), 4.90 (br s, 2H), 7.27 (d,J=8.20 Hz, 2H), 7.37 (d, J=8.20 Hz, 1H), 7.43 (s, 1H), 7.49 (d, J=8.20Hz, 2H), 7.86 (d, J=8.20 Hz, 1H); MS (ESI) [M+1]⁺ 461.

Example C-40:2-((1r,4r)-4-(4-(1-(piperidine-1-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 1.18-1.39 (m, 2H), 1.54-1.64 (m,2H), 1.64-1.76 (m, 6H), 1.81-1.99 (m, 5H), 2.25 (d, J=6.94 Hz, 2H),2.49-2.58 (m, 1H), 3.11 (t, J=8.20 Hz, 2H), 3.41 (d, J=5.04 Hz, 4H),3.94 (t, J=8.20 Hz, 2H), 4.90 (br s, 1H), 7.06 (d, J=8.51 Hz, 1H),7.25-7.30 (m, 2H), 7.40 (m, 1H), 7.46-7.52 (m, 3H); MS (ESI) [M+1]⁺ 447.

Example C-41:2-((1r,4r)-4-(4-(1-(cyclopentylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (m, 2H), 1.50 (m, 6H), 1.68 (m,3H), 1.83 (m, 6H), 2.15 (d, J=6.31 Hz, 2H), 2.52 (m, 1H), 3.15 (t,J=8.51 Hz, 2H), 3.92 (t, J=8.51 Hz, 2H), 4.03 (m, 1H), 6.36 (d, J=6.62Hz, 1H), 7.26 (d, J=7.57 Hz, 2H), 7.36 (d, J=7.88 Hz, 1H), 7.42 (br s,1H), 7.51 (d, J=7.25 Hz, 2H), 7.86 (d, J=8.20 Hz, 1H), 12.05 (br s, 1H);MS (ESI) [M+1]⁺ 447.

Example C-42: 2-((1r,4r)-4-(4-(indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.08-1.18 (m, 2H), 1.43-1.54 (m, 2H),1.74 (m, 1H), 1.83 (m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.55 (m, 1H), 3.09(t, J=7.88 Hz, 2H), 3.32 (br s, 1H), 3.90 (t, J=7.88 Hz, 2H), 6.97 (brs, 1H), 7.28 (d, J=7.88 Hz, 2H), 7.39 (d, J=7.57 Hz, 1H), 7.45-7.64 (m,3H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺ 336.

Example C-43:2-((1r,4r)-4-(4-(1-benzoylindolin-5-yl)phenyl)cyclohexyl)acetic acid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.08-1.18 (m, 2H), 1.55-1.44 (m, 2 H),1.70-1.78 (m, 1H), 1.78-1.87 (m, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.55 (m,1H), 3.16 (t, J=8.80 Hz, 2H), 4.05 (m, 2H), 7.30 (d, J=7.88 Hz, 2H),7.47-7.66 (m, 10H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 440.

Example C-44:2-((1r,4r)-4-(4-(1-(phenylcarbamothioyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.56 Hz, 2H), 1.49 (q,J=11.56 Hz, 2H), 1.75 (m, 1H), 1.82 (m, 4H), 2.16 (d, J=6.94 Hz, 2H),2.48 (m, 1H), 3.17 (t, J=7.88 Hz, 2H), 4.33 (t, J=7.88 Hz, 2H), 7.15 (t,J=7.09 Hz, 1H), 7.30 (d, J=8.20 Hz, 2H), 7.35 (t, J=8.05 Hz, 2H),7.40-7.48 (m, 3H), 7.52-7.61 (m, 3H), 8.16 (d, J=8.51 Hz, 1H), 9.81 (s,1H), 11.99 (br s, 1H); MS (ESI) [M+1]⁺ 471.

Example C-45:2-((1r,4r)-4-(4-(1-(2-phenylacetyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.06-1.20 (m, 2H), 1.43-1.54 (m, 2H),1.69-1.76 (m, 1H), 1.77-1.88 (m, 4H), 2.14 (d, J=5.99 Hz, 2H), 2.44-2.59(m, 1H), 3.21 (t, J=7.50 Hz, 2H), 3.87 (s, 2H), 4.21 (t, J=7.50 Hz, 2H),7.21-7.39 (m, 7H), 7.43 (d, J=7.88 Hz, 1H), 7.48-7.57 (m, 3H), 8.10 (d,J=8.20 Hz, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]⁺ 454.

Example C-46:2-((1r,4r)-4-(4-(1-(morpholine-4-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (m, 2H), 1.48 (m, 2H), 1.67-1.88(m, 5H), 2.14 (d, J=6.40 Hz, 2H), 2.42-2.57 (m, 1H), 3.06 (br s, 2H),3.29 (br s, 4H), 3.66 (br s, 4H), 3.89 (br s, 2H), 7.13 (d, J=7.57 Hz,1H), 7.27 (d, J=6.62 Hz, 2H), 7.40 (d, J=7.57 Hz, 1H), 7.45-7.59 (m,3H), 12.20 (br s, 1H); MS (ESI) [M+1]⁺ 449.

Example C-47:2-((1r,4r)-4-(4-(1-(1H-imidazole-2-carbonyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.45 Hz, 2H), 1.50 (q,J=11.98 Hz, 2H), 1.75 (br s, 1H), 1.83 (m, 4H), 2.16 (d, J=6.62 Hz, 2H),2.48 (m, 1H), 3.25 (t, J=8.20 Hz, 2H), 3.36 (br s, 1H), 4.79 (t, J=7.88Hz, 2H), 7.30 (d, J=7.57 Hz, 4H), 7.51 (d, J=8.51 Hz, 1H), 7.54-7.62 (m,3H), 8.28 (d, J=7.57 Hz, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]⁺ 430.

Example C-48:2-((1r,4r)-4-(4-(1-heptanoylindolin-5-yl)phenyl)cyclohexyl)acetic acid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.84-0.91 (m, 3H), 1.07-1.18 (m, 2H),1.29 (m, 6H), 1.41-1.53 (m, 4H), 1.70-1.78 (m, 1H), 1.78-1.86 (m, 4H),2.15 (d, J=6.62 Hz, 2H), 2.48 (m, 1H), 3.11 (q, J=6.55 Hz, 2H), 3.16 (t,J=8.50 Hz, 2H), 3.90 (t, J=8.60 Hz, 2H), 6.64 (t, J=5.20 Hz, 1H), 7.26(d, J=7.88 Hz, 2H), 7.36 (br d, J=8.51 Hz, 1H), 7.42 (s, 1H), 7.50 (d,J=7.88 Hz, 2H), 7.87 (d, J=8.20 Hz, 1H), 11.99 (br s, 1H); MS (ESI)[M+1]⁺ 463.

Example C-49:2-((1r,4r)-4-(4-(1-(diisopropylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.06-1.18 (m, 2H), 1.29 (d, J=6.60 Hz,12H), 1.48 (q, J=11.60 Hz, 2H), 1.68-1.78 (m, 1H), 1.83 (t, J=11.66 Hz,4H), 2.10 (d, J=6.94 Hz, 2H), 2.47 (m, 1H), 3.07 (t, J=8.10 Hz, 2H),3.78 (m, 2H), 3.79 (t, J=7.95 Hz, 2H), 6.94 (d, J=8.20 Hz, 1H), 7.26 (d,J=7.57 Hz, 2H), 7.35 (d, J=8.20 Hz, 1H), 7.44 (s, 1H), 7.49 (d, J=7.57Hz, 2H), 12.50 (br s, 1H); MS (ESI) [M+1]⁺ 463.

Example C-50:2-((1r,4r)-4-(4-(2-(phenylcarbamoyl)-1H-indol-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.05-1.24 (m, 2H), 1.36-1.57 (m, 2H),1.68-1.79 (m, 1H), 1.79-1.88 (m, 4H), 2.14 (m, 1H), 2.16 (d, J=6.94 Hz,2H), 7.12 (t, J=7.25 Hz, 1H), 7.31 (m, 2H), 7.39 (t, J=7.88 Hz, 2H),7.49 (d, J=2.22 Hz, 1H), 7.51-7.55 (m, 2H), 7.61 (d, J=8.20 Hz, 2H),7.83 (d, J=7.88 Hz, 2H), 7.92 (s, 1H), 10.26 (s, 1H), 11.81 (br s, 1H),11.99 (br s, 1H); MS (ESI) [M+1]⁺ 453.

Example C-51:2-((1r,4r)-4-(4-(1-(4-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.80 Hz, 2H), 1.49 (q,J=11.87 Hz, 2H), 1.70-1.79 (m, 1H), 1.79-1.90 (m, 4H), 2.16 (d, J=6.94Hz, 2H), 2.47 (m, 1H), 3.24 (t, J=8.51 Hz, 2H), 4.17 (t, J=8.51 Hz, 2H),7.28 (d, J=7.57 Hz, 2H), 7.36 (d, J=8.51 Hz, 2H), 7.43 (d, J=8.51 Hz,1H), 7.49 (s, 1H), 7.53 (d, J=8.00 Hz, 2H), 7.63 (d, J=8.51 Hz, 2H),7.91 (d, J=8.55 Hz, 1H), 8.69 (s, 1H), 12.03 (br s, 1H); MS (ESI) [M+1]⁺489.

Example C-52:2-((1r,4r)-4-(4-(1-(3,5-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q,J=11.35 Hz, 2H), 1.69-1.77 (m, 1H), 1.77-1.88 (m, 4H), 2.15 (d, J=5.99Hz, 2H), 2.48 (m, 1H), 3.24 (t, J=8.20 Hz, 2H), 4.17 (t, J=8.20 Hz, 2H),6.84 (t, J=8.35 Hz, 1H), 7.28 (d, J=7.25 Hz, 2H), 7.35-7.47 (m, 3H),7.50 (s, 1H), 7.53 (d, J=7.57 Hz, 2H), 7.92 (d, J=8.20 Hz, 1H), 8.91 (brs, 1H), 12.18 (br s, 1H); MS (ESI) [M+1]⁺ 491.

Example C-53:2-((1r,4r)-4-(4-(1-(2,6-difluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.35 Hz, 2H), 1.48 (q,J=11.35 Hz, 2H), 1.69-1.79 (m, 1H), 1.79-1.87 (m, 4H), 2.15 (d, J=6.62Hz, 2H), 2.47 (m, 1H), 3.27 (t, J=8.35 Hz, 2H), 4.15 (t, J=8.20 Hz, 2H),7.11-7.22 (m, 3H), 7.30 (d, J=7.30 Hz, 2H), 7.41 (d, J=8.15 Hz, 1H),7.50 (s, 1H), 7.53 (d, J=7.25 Hz, 2H), 7.84 (d, J=8.20 Hz, 1H), 8.46 (brs, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 491.

Example C-54:2-((1r,4r)-4-(4-(1-(2-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.30 Hz, 2H), 1.49 (q,J=11.30 Hz, 2H), 1.70-178 (m, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.62Hz, 2H), 2.47 (m, 1H), 3.27 (t, J=8.51 Hz, 2H), 4.20 (t, J=8.51 Hz, 2H),7.23 (br t, J=7.60 Hz, 1H), 7.28 (d, J=7.25 Hz, 2H), 7.36 (br t, J=8.05Hz, 1H), 7.42 (d, J=8.51 Hz, 1H), 7.50 (s, 1H), 7.53 (m, 3H), 7.67 (d,J=7.88 Hz, 1H), 7.88 (d, J=8.51 Hz, 1H), 8.30 (br s, 1H), 12.04 (br s,1H); MS (ESI) [M+1]⁺ 489

Example C-55:2-((1r,4r)-4-(4-(1-(3-chlorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.09-1.19 (m, 2H), 1.49 (q, J=11.35 Hz,2H), 1.71-1.78 (m, 1H), 1.79-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.47(m, 1H), 3.24 (t, J=8.50 Hz, 2H), 4.18 (t, J=8.51 Hz, 2H), 7.07 (d,J=7.88 Hz, 1H), 7.28 (d, J=7.29 Hz, 2H), 7.33 (t, J=8.20 Hz, 1H), 7.44(d, J=7.88 Hz, 1H), 7.50 (s, 1H), 7.52-7.57 (m, 3H), 7.78 (br s, 1H),7.91 (d, J=8.20 Hz, 1H), 8.73 (s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]⁺489.

Example C-56:2-((1r,4r)-4-(4-(1-(2-methoxyphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.50 Hz, 2H), 1.49 (q,J=11.77 Hz, 2H), 1.68-1.77 (m, 1H), 1.77-1.88 (m, 4H), 2.14 (d, J=5.99Hz, 2H), 2.47 (m, 1H), 3.24 (t, J=8.30 Hz, 2H), 3.86 (s, 3H), 4.16 (t,J=8.20 Hz, 2H), 6.94 (t, J=6.46 Hz, 1H), 7.01-7.15 (m, 2H), 7.28 (d,J=7.57 Hz, 2H), 7.42 (d, J=8.20 Hz, 1H), 7.49 (s, 1H), 7.53 (d, J=7.88Hz, 2H), 7.72 (s, 1H), 7.83 (d, J=7.57 Hz, 1H), 7.90 (d, J=8.20 Hz, 1H),12.05 (br s, 1H); MS (ESI) [M+1]⁺ 485.

Example C-57:2-((1r,4r)-4-(4-(1-(4-methoxyphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q,J=11.77 Hz, 2H), 1.69-1.78 (m, 1H), 1.78-1.89 (m, 4H), 2.14 (d, J=6.31Hz, 2H), 2.47 (m, 1H), 3.22 (t, J=8.35 Hz, 2H), 3.74 (s, 3H), 4.14 (t,J=8.51 Hz, 2H), 6.89 (d, J=8.83 Hz, 2H), 7.27 (d, J=7.88 Hz, 2H), 7.40(d, J=8.51 Hz, 1H), 7.45 (d, J=8.83 Hz, 2H), 7.47 (s, 1H), 7.52 (d,J=7.88 Hz, 2H), 7.90 (d, J=8.51 Hz, 1H), 8.43 (s, 1H), 12.10 (br s, 1H);MS (ESI) [M+1]⁺ 485.

Example C-58:2-((1r,4r)-4-(4-(1-(benzylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q,J=11.35 Hz, 2H), 1.69-1.78 (m, 1H), 1.78-1.87 (m, 4H), 2.13 (d, J=6.10Hz, 2H), 2.47 (m, 1H), 3.19 (t, J=7.95 Hz, 2H), 3.99 (t, J=8.10 Hz, 2H),4.33 (m, 2H), 7.14 (d, J=6.90 Hz, 1H), 7.19-7.38 (m, 7H), 7.44 (s, 1H),7.51 (d, J=7.88 Hz, 2H), 7.88 (d, J=7.57 Hz, 1H), 8.79 (br s, 1H), 12.40(br s, 1H); MS (ESI) [M+1]⁺ 469.

Example C-59:2-((1r,4r)-4-(4-(1-(3-methoxyphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.06-1.18 (m, 2H), 1.43-1.54 (m, 2H),1.68-1.78 (m, 1H), 1.78-1.88 (m, 4H), 2.15 (br s, 2H), 2.47 (m, 1H),3.23 (t, J=8.50 Hz, 2H), 3.95 (s, 3H), 4.17 (t, J=8.10 Hz, 2H), 6.60 (brs, 1H), 7.14-7.21 (m, 2H), 7.23-7.32 (m, 3H), 7.42 (d, J=7.57 Hz, 1H),7.49 (s, 1H), 7.53 (d, J=7.88 Hz, 2H), 7.88 (d, J=8.15 Hz, 1H), 8.52 (s,1H), 12.25 (br s, 1H); MS (ESI) [M+1]⁺ 485.

Example C-60:2-((1r,4r)-4-(4-(1-(1-adamantylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.67 Hz, 2H), 1.48 (q,J=11.80 Hz, 2H), 1.59 (br s, 2H), 1.65 (br s, 4H), 1.72-1.78 (m, 1H),1.78-1.87 (m, 6H), 1.97 (br s, 2H), 2.00-2.07 (m, 5H), 2.15 (d, J=6.62Hz, 2H), 2.47 (m, 1H), 3.12 (t, J=8.35 Hz, 2H), 3.93 (t, J=8.51 Hz, 2H),5.36 (br s, 1H), 7.26 (d, J=6.94 Hz, 2H), 7.35 (dd, J=1.89, 8.20 Hz,1H), 7.42 (s, 1H), 7.51 (d, J=6.94 Hz, 2H), 7.81 (d, J=8.20 Hz, 1H),12.08 (br s, 1H); MS (ESI) [M+1]⁺ 513.

Example C-61:2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q,J=11.66 Hz, 2H), 1.74 (br s, 1H), 1.77-1.88 (m, 4H), 2.12 (d, J=6.31 Hz,2H), 2.47 (m, 1H), 3.91 (br s, 2H), 4.32 (br s, 2H), 7.15-7.23 (m, 3H),7.29 (d, J=7.25 Hz, 2H), 7.34 (t, J=7.57 Hz, 1H), 7.50 (d, J=8.20 Hz,1H), 7.55 (d, J=7.88 Hz, 2H), 7.68 (d, J=8.20 Hz, 1H), 7.71 (d, J=8.51Hz, 1H), 8.79 (br s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]⁺ 505.

Example C-62:2-((1r,4r)-4-(4-(4-(3-fluorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.35 Hz, 2H), 1.48 (q,J=11.66 Hz, 2H), 1.74 (br s, 1H), 1.78-1.87 (m, 4H), 2.14 (d, J=6.00 Hz,2H), 2.47 (m, 1H), 3.88 (br s, 2H), 4.30 (br s, 2H), 6.82 (m, 1H), 7.16(br s, 2H), 7.26-7.34 (m, 4H), 7.45 (d, J=11.40 Hz, 1H), 7.50-7.61 (m,3H), 9.41 (br s, 1H), 12.20 (br s, 1H); MS (ESI) [M+1]⁺ 489.

Example C-63:2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88 (t, J=7.25 Hz, 3H), 1.12 (q,J=11.35 Hz, 2H), 1.23-1.33 (m, 6H), 1.43-1.53 (m, 4H), 1.74 (br s, 1H),1.78-1.86 (m, 4H), 2.14 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.10 (m, 2H),3.72 (t, J=3.57 Hz, 2H), 4.20 (t, J=4.10 Hz, 2H), 6.96 (t, J=4.70 Hz,1H), 7.11 (s, 1H), 7.13 (d, J=7.88 Hz, 1H), 7.28 (d, J=7.88 Hz, 2H),7.52 (d, J=7.57 Hz, 2H), 7.63 (d, J=8.51 Hz, 1H), 12.05 (br s, 1H); MS(ESI) [M+1]⁺ 479.

Example C-64:2-((1r,4r)-4-(4-(1-(N-phenylsulfamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.60 Hz, 2H), 1.48 (q,J=11.70 Hz, 2H), 1.74 (br s, 1H), 1.77-1.88 (m, 4H), 2.15 (d, J=6.31 Hz,2H), 2.47 (m, 1H), 3.03 (t, J=7.41 Hz, 2H), 3.93 (t, J=7.88 Hz, 2H),7.02 (t, J=6.62 Hz, 1H), 7.14 (d, J=7.25 Hz, 2H), 7.20-7.31 (m, 4H),7.34 (d, J=8.20 Hz, 1H), 7.38-7.46 (m, 2H), 7.49 (d, J=7.25 Hz, 2H),10.70 (br s, 1H), 12.00 (br s, 1H); MS (ESI) [M+1]⁺ 491.

Example C-65:2-((1r,4r)-4-(4-(4-(benzylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.77 Hz, 2H), 1.49 (q,J=11.55 Hz, 2H), 1.71-1.79 (m, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.94Hz, 2H), 2.47 (m, 1H), 3.67 (t, J=4.10 Hz, 2H), 4.16 (t, J=4.10 Hz, 2H),4.74 (s, 2H), 7.13 (d, J=8.80 Hz, 1H), 7.16 (br s, 1H), 7.30 (d, J=7.57Hz, 2H), 7.33-7.40 (m, 5H), 7.54 (d, J=7.88 Hz, 2H), 7.62 (d, J=7.57 Hz,1H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺ 506.

Example C-66:2-((1r,4r)-4-(4-(4-(2-chlorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.05 (q, J=11.70 Hz, 2H), 1.39 (q,J=11.77 Hz, 2H), 1.62 (d, J=11.98 Hz, 2H), 1.67-1.72 (m, 1H), 1.75 (d,J=11.66 Hz, 2H), 2.19 (d, J=6.94 Hz, 2H), 2.41 (t, J=11.98 Hz, 1H), 3.31(t, J=4.10 Hz, 2H), 4.14 (t, J=3.98 Hz, 2H), 6.61 (d, J=8.20 Hz, 1H),6.91 (br s, 1H), 6.96 (d, J=8.20 Hz, 1H), 7.19 (d, J=7.88 Hz, 2H), 7.41(d, J=7.88 Hz, 2H), 7.61 (br t, J=7.10 Hz, 1H), 7.67-7.75 (m, 2H), 8.11(d, J=7.88 Hz, 1H), 12.47 (br s, 1H); MS (ESI) [M+1]⁺ 525.

Example C-67:2-((1r,4r)-4-(4-(4-(biphenyl-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.20-1.33 (m, 2H), 1.60 (q, J=11.40Hz, 2H), 1.91-1.97 (m, 1H), 1.98-2.06 (m, 4H), 2.36 (d, J=6.94 Hz, 2H),2.58 (t, J=11.98 Hz, 1H), 3.94 (t, J=4.10 Hz, 2H), 4.30 (t, J=4.25 Hz,2H), 6.58 (br s, 1H), 6.71 (dd, J=2.00, 8.20 Hz, 1H), 6.77 (d, J=8.20Hz, 1H), 7.10 (d, J=1.95 Hz, 1H), 7.16 (br t, J=7.40 Hz, 1H), 7.22 (brd, J=7.60 Hz, 1H), 7.24-7.36 (m, 6H), 7.41 (t, J=7.60 Hz, 1H), 7.46 (d,J=8.20 Hz, 2H), 7.60 (s, 1H), 8.28 (d, J=8.20 Hz, 1H), 12.00 (br s, 1H);MS (ESI) [M+1]⁺ 547.

Example C-68:2-((1r,4r)-4-(4-(4-(tert-butylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.80 Hz, 2H), 1.32 (s, 9H),1.49 (q, J=11.50 Hz, 2H), 1.70-1.78 (m, 1H), 1.79-1.87 (m, 4H), 2.16 (d,J=6.62 Hz, 2H), 2.47 (m, 1H), 3.70 (t, J=4.20 Hz, 2H), 4.19 (q, J=4.10Hz, 2H), 6.36 (s, 1H), 7.10 (br s, 1H), 7.13 (br d, J=8.45 Hz, 1H), 7.28(d, J=7.88 Hz, 2H), 7.52 (d, J=7.80 Hz, 2H), 7.56 (br d, J=8.51 Hz, 1H),12.05 (br s, 1H); MS (ESI) [M+1]⁺ 451.

Example C-69:2-((1r,4r)-4-(4-(4-(isopropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.07-1.19 (m, 2H), 1.14 (d, J=6.10 Hz,6H), 1.48 (q, J=11.60 Hz, 2H), 1.70-1.77 (m, 1H), 1.79-1.87 (m, 4H),2.15 (d, J=6.31 Hz, 2H), 2.47 (m, 1H), 3.72 (br s, 2H), 3.85 (h, J=6.20Hz, 1H), 4.20 (br s, 2H), 6.71 (d, J=7.25 Hz, 1H), 7.10 (s, 1H), 7.13(d, J=8.51 Hz, 1H), 7.27 (d, J=7.57 Hz, 2H), 7.52 (d, J=7.57 Hz, 2H),7.65 (d, J=8.20 Hz, 1H), 12.35 (br s, 1H); MS (ESI) [M+1]⁺ 437.

Example C-70:2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.60 Hz, 2H), 1.50 (q,J=11.55 Hz, 2H), 1.70-1.78 (br s, 1H), 1.79-1.87 (m, 4H), 2.16 (d,J=6.62 Hz, 2H), 2.44-2.48 (m, 1H), 3.92 (br s, 2H), 4.43 (br s, 2H),7.03 (t, J=7.25 Hz, 1H), 7.28-7.33 (m, 4H), 7.50 (d, J=7.88 Hz, 2H),7.54 (d, J=8.51 Hz, 1H), 7.91 (d, J=7.88 Hz, 2H), 8.05 (d, J=8.20 Hz,1H), 9.23 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 472.

Example C-71:2-((1r,4r)-4-(4-(1-(4-methylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.40 Hz, 2H), 1.75 (br s, 1H), 1.78-1.87 (m, 4H), 2.16 (d, J=6.94 Hz,2H), 2.27 (s, 3H), 2.44-2.49 (m, 1H), 3.23 (t, J=8.20 Hz, 2H), 4.16 (t,J=8.20 Hz, 2H), 7.11 (d, J=8.20 Hz, 2H), 7.28 (d, J=8.20 Hz, 2H), 7.41(d, J=8.50 Hz, 1H), 7.45 (d, J=8.20 Hz, 2H), 7.48 (s, 1H), 7.53 (d,J=8.20 Hz, 2H), 7.91 (d, J=8.51 Hz, 1H), 8.46 (s, 1H), 12.06 (br s, 1H);MS (ESI) [M+1]⁺ 469.

Example C-72:2-((1r,4r)-4-(4-(1-(2-fluorophenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.35 Hz, 2H), 1.75 (br s, 1H), 1.79-1.87 (m, 4H), 2.16 (d, J=6.94 Hz,2H), 2.45-2.49 (m, 1H), 3.25 (t, J=8.51 Hz, 2H), 4.17 (t, J=8.51 Hz,2H), 7.17-7.27 (m, 3H), 7.28 (d, J=8.20 Hz, 2H), 7.42 (d, J=8.51 Hz,1H), 7.50 (s, 1H), 7.53-7.56 (m, 1H), 7.53 (d, J=8.20 Hz, 2H), 7.87 (d,J=8.51 Hz, 1H), 8.41 (s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]⁺ 473.

Example C-73:2-((1r,4r)-4-(4-(1-(benzo[d][1,3]dioxol-5-ylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.35 Hz, 2H), 1.74 (br s, 1H), 1.79-1.88 (m, 4H), 2.15 (d, J=6.95 Hz,2H), 2.45-2.50 (m, 1H), 3.23 (t, J=8.51 Hz, 2H), 4.13 (t, J=8.51 Hz,2H), 5.99 (s, 2H), 6.86 (d, J=8.51 Hz, 1H), 6.96 (dd, J=1.89 and 8.51Hz, 1H), 7.22 (d, J=1.89 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H), 7.41 (d,J=8.51 Hz, 1H), 7.48 (s, 1H), 7.53 (d, J=8.20 Hz, 2H), 7.89 (d, J=8.51Hz, 1H), 8.45 (s, 1H), 12.17 (br s, 1H); MS (ESI) [M+1]⁺ 499.

Example C-74:2-((1r,4r)-4-(4-(1-(4-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.49 (q,J=11.35 Hz, 2H), 1.75 (br s, 1H), 1.79-1.88 (m, 4H), 2.16 (d, J=6.94 Hz,2H), 2.45-2.50 (m, 1H), 3.25 (t, J=8.50 Hz, 2H), 4.21 (t, J=8.50 Hz,2H), 7.29 (d, J=8.20 Hz, 2H), 7.44 (d, J=8.51 Hz, 1H), 7.51 (s, 1H),7.54 (d, J=8.00 Hz, 2H), 7.67 (d, J=8.51 Hz, 2H), 7.84 (d, J=8.51 Hz,2H), 7.93 (d, J=8.51 Hz, 1H), 8.93 (s, 1H), 12.06 (br s, 1H); MS (ESI)[M+1]⁺ 523.

Example C-75:2-((1r,4r)-4-(4-(1-(2-trifluoromethylphenylcarbamoyl)indolin-5-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.40 Hz, 2H), 1.48 (q,J=11.40 Hz, 2H), 1.74 (br s, 1H), 1.78-1.86 (m, 4H), 2.15 (d, J=6.94 Hz,2H), 2.44-2.49 (m, 1H), 3.26 (t, J=8.51 Hz, 2H), 4.14 (t, J=8.51 Hz,2H), 7.27 (d, J=8.20 Hz, 2H), 7.40 (d, J=8.51 Hz, 1H), 7.48 (t, J=7.57Hz, 1H), 7.49 (s, 1H), 7.52 (d, J=8.20 Hz, 2H), 7.59 (d, J=7.88 Hz, 1H),7.71 (t, J=7.88 Hz, 1H), 7.75 (d, J=7.88 Hz, 1H), 7.84 (d, J=8.51 Hz,1H), 8.36 (s, 1H), 12.03 (br s, 1H); MS (ESI) [M+1]⁺ 523.

Example C-76:2-((1r,4r)-4-(4-(4-(m-tolylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.24 (q, J=11.98 Hz, 2H), 1.59 (q,J=11.98 Hz, 2H), 1.93 (br s, 1H), 2.00 (br d, J=11.98 Hz, 4H), 2.35 (d,J=6.94 Hz, 2H), 2.37 (s, 3H), 2.52-2.60 (m, 1H), 4.01 (t, J=4.41 Hz,2H), 4.37 (t, J=4.41 Hz, 2H), 6.91-6.93 (m, 1H), 7.19-7.26 (m, 5H),7.27-7.30 (m, 1H), 7.31 (d, J=8.20 Hz, 2H), 7.40 (d, J=8.20 Hz, 1H),7.54 (d, J=8.50 Hz, 2H), 9.85 (br s, 1H); MS (ESI) [M+1]⁺ 485.

Example C-77:2-((1r,4r)-4-(4-(4-(2-fluorophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.40 Hz, 2H), 1.49 (q,J=11.40 Hz, 2H), 1.75 (br s, 1H), 1.78-1.87 (m, 4H), 2.16 (d, J=6.95 Hz,2H), 2.46-2.50 (m, 1H), 3.89 (t, J=4.10 Hz, 2H), 4.31 (t, J=4.10 Hz,2H), 7.13-7.20 (m, 4H), 7.22-7.27 (m, 1H), 7.29 (d, J=8.20 Hz, 2H), 7.54(d, J=8.20 Hz, 2H), 7.52-7.59 (m, 1H), 7.67 (d, J=8.10 Hz, 1H), 8.87 (s,1H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺ 489.

Example C-78:2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.24 Hz, 2H), 1.35 (d,J=5.99 Hz, 3H), 1.49 (q, J=11.20 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d,J=7.57 Hz, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.42-2.49 (m, 1H), 3.41 (dd,J=13.24, 12.93 Hz, 1H), 4.08 (d, J=12.61 Hz, 1H), 4.39 (br t, J=6.20 Hz,1H), 7.16 (s, 1H), 7.17 (d, J=9.50 Hz, 1H), 7.29 (d, J=7.88 Hz, 2H),7.58 (d, J=6.31 Hz, 2H), 7.55 (d, J=7.88 Hz, 2H), 7.65 (m, 2H), 8.82 (s,1H), 12.06 (br s, 1H); MS (ESI) [M+1]⁺ 571. The two enantiomers wereresolved by chiral HPLC (isocratic mode, 1 mL/min on Varian system 1;hexanes:isopropanol:methylene chloride 87.3:2.7:10): enantiomer A(rt=12.35 min); enantiomer B (rt=14.03 min).

Example C-79:2-((1r,4r)-4-(4-(2-methyl-4-(2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.90 Hz, 2H), 1.36 (d,J=5.99 Hz, 3H), 1.49 (q, J=11.90 Hz, 2H), 1.69-1.78 (m, 1H), 1.79-1.87(m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.42-2.49 (m, 1H), 3.42 (dd, J=13.40,7.41 Hz, 1H), 4.10 (d, J=11.66 Hz, 1H), 4.39 (t, J=5.83 Hz, 1H), 7.17(s, 1H), 7.18 (d, J=9.70 Hz, 1H), 7.29 (d, J=8.20 Hz, 2H), 7.46 (t,J=7.57 Hz, 1H), 7.53-7.59 (m, 3H), 7.65 (d, J=7.88 Hz, 1H), 7.69 (t,J=7.66 Hz, 1H), 7.74 (d, J=8.04 Hz, 1H), 8.78 (s, 1H), 12.06 (br s, 1H);MS (ESI) [M+1]⁺ 553.

Example C-80:2-((1r,4r)-4-(4-(2-isopropyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98 (d, J=6.62 Hz, 3H), 1.07 (d, J=6.62Hz, 3H), 1.13 (q, J=11.77 Hz, 2H), 1.49 (q, J=11.77 Hz, 2H), 1.70-1.77(m, 1H), 1.78-1.86 (m, 4H), 1.94 (m, 1H), 2.15 (d, J=6.62 Hz, 2H),2.41-2.49 (m, 1H), 3.53 (dd, J=13.40, 7.41 Hz, 1H), 3.93 (br t, J=6.45Hz, 1H), 4.04 (d, J=12.61 Hz, 1H), 7.01 (t, J=7.09 Hz, 1H), 7.13-7.19(m, 2H), 7.25-7.32 (m, 4H), 7.47-7.58 (m, 5H), 9.18 (s, 1H), 12.07 (brs, 1H); MS (ESI) [M+1]⁺ 513.

Example C-81:2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12-1.18 (m, 2H), 1.16 (t, J=7.57 Hz,3H), 1.37 (d, J=5.99 Hz, 3H), 1.49 (q, J=11.35 Hz, 2H), 1.70-1.78 (m,1H), 1.78-1.87 (m, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.44-2.49 (m, 1H), 2.60(q, J=7.57 Hz, 2H), 3.41 (dd, J=13.56, 7.57 Hz, 1H), 4.10 (d, J=12.30Hz, 1H), 4.39 (t, J=5.67 Hz, 1H), 7.12-7.22 (m, 4H), 7.22-7.32 (m, 4H),7.54 (d, J=7.88 Hz, 2H), 7.67 (d, J=8.20 Hz, 1H), 8.57 (s, 1H), 12.06(br s, 1H); MS (ESI) [M+1]⁺ 513. The two enantiomers were resolved bychiral HPLC (isocratic mode, 1 mL/min on Varian system 1;hexanes:isopropanol 90:10): enantiomer A (R absolute configuration,rt=23.32 min); enantiomer B (S absolute configuration, rt=28.64 min).

Example C-82:2-((1r,4r)-4-(4-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.13 (q,J=11.66 Hz, 2H), 1.49 (q, J=11.66 Hz, 2H), 1.62-1.77 (m, 3H), 1.78-1.87(m, 4H), 2.15 (d, J=6.31 Hz, 2H), 2.41-2.49 (m, 1H), 3.47 (dd, J=12.61,7.25 Hz, 1H), 4.03 (d, J=12.61 Hz, 1H), 4.16 (br s, 1H), 7.00 (t, J=7.41Hz, 1H), 7.16 (br s, 2H), 7.26-7.33 (m, 4H), 7.45-7.59 (m, 5H), 9.17 (brs, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]⁺ 499. The two enantiomers wereresolved by chiral HPLC (isocratic mode, 1 mL/min on Varian system 1;hexanes:isopropanol 90:10): enantiomer A (rt=20.02 min); enantiomer B(rt=20.86 min).

Example C-83:2-((1r,4r)-4-(4-(2-(phenylamino)quinoxalin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.51 Hz, 2H), 1.52 (q,J=11.51 Hz, 2H), 1.71-1.80 (m, 1H), 1.81-1.86 (m, 4H), 2.17 (d, J=6.94Hz, 2H), 2.45-2.49 (m, 1H), 3.32 (s, 1H), 7.05 (t, J=7.41 Hz, 1H),7.35-7.42 (m, 3H), 7.73 (d, J=7.88 Hz, 2H), 7.80 (d, J=8.51 Hz, 1H),7.98 (d, J=8.65 Hz, 1H), 8.00 (d, J=7.88 Hz, 2H), 8.09 (s, 1H), 8.60 (s,1H), 10.00 (s, 1H), 12.06 (s, 1H); MS (ESI) [M+1]⁺ 438.

Example C-84:2-((1r,4r)-4-(4-(4-(4-chloro-2-fluorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=12.40 Hz, 2H), 1.35 (d,J=6.31 Hz, 3H), 1.49 (q, J=12.40 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d,J=10.56 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.49 (br s, 1H), 3.38 (dd,J=13.57, 7.72 Hz, 1H), 4.11 (d, J=11.35 Hz, 1H), 4.38 (br t, J=6.31 Hz,1H), 7.16 (s, 1H), 7.17 (d, J=10.20 Hz, 1H), 7.26 (br d, J=8.99 Hz, 1H),7.29 (d, J=8.04 Hz, 2H), 7.48 (dd, J=10.70, 2.21 Hz, 1H), 7.53-7.58 (m,3H), 7.64 (d, J=8.20 Hz, 1H), 9.00 (s, 1H), 12.06 (br s, 1H); MS (ESI)[M+1]⁺ 538.

Example C-85:2-((1r,4r)-4-(4-(4-(4-fluoro-3-methylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.82 Hz, 2H), 1.35 (d,J=5.99 Hz, 3H), 1.49 (q, J=11.82 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d,J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.21 (s, 3H), 2.44-2.49 (m,1H), 3.28-3.35 (m, 1H), 4.09 (d, J=11.82 Hz, 2H), 4.35 (br t, J=6.85 Hz,1H), 7.06 (t, J=9.14 Hz, 1H), 7.15 (s, 1H), 7.16 (d, J=9.30 Hz, 1H),7.29 (d, J=8.36 Hz, 2H), 7.40 (dd, J=2.36, 7.09 Hz, 1H), 7.54 (d, J=8.04Hz, 2H), 7.56 (d, J=7.72 Hz, 1H), 9.12 (s, 1H), 12.04 (br s, 1H); MS(ESI) [M+1]⁺ 517.

Example C-86:2-((1r,4r)-4-(4-(4-(3-chloro-4-fluorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.35 Hz, 2H), 1.35 (d,J=6.31 Hz, 3H), 1.49 (q, J=11.35 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d,J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.43-2.50 (m, 1H), 3.34-3.39(m, 1H), 4.10 (dd, J=13.20, 2.36 Hz, 1H), 4.36 (dt, J=2.36, 5.80 Hz,1H), 7.16 (s, 1H), 7.17 (dd, J=1.73, 8.99 Hz, 1H), 7.29 (d, J=8.20 Hz,2H), 7.36 (t, J=8.99 Hz, 1H), 7.44-7.48 (m, 1H), 7.53-7.58 (m, 3H), 7.77(dd, J=2.68, 6.94 Hz, 1H), 9.37 (s, 1H), 12.07 (br s, 1H); MS (ESI)[M+1]⁺ 538.

Example C-87:2-((1r,4r)-4-(4-(4-(2,4-dimethylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=12.10 Hz, 2H), 1.36 (d,J=6.31 Hz, 3H), 1.49 (q, J=12.10 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d,J=9.77 Hz, 4H), 2.16 (d, J=7.09 Hz, 2H), 2.18 (s, 3H), 2.26 (s, 3H),2.45-2.50 (m, 1H), 3.38 (dd, J=7.88, 13.56 Hz, 1H), 4.09 (dd, J=2.04,13.08 Hz, 1H), 4.37 (dt, J=2.04, 7.08 Hz, 1H), 6.97 (d, J=8.51 Hz, 1H),7.03 (s, 1H), 7.13-7.18 (m, 3H), 7.28 (d, J=8.20 Hz, 2H), 7.54 (d,J=8.20 Hz, 2H), 7.68 (d, J=8.51 Hz, 1H), 8.54 (s, 1H), 12.06 (br s, 1H);MS (ESI) [M+1]⁺ 513.

Example C-88:2-((1r,4r)-4-(4-(4-(2-methoxy-5-methylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.82 Hz, 2H), 1.35 (d,J=6.31 Hz, 3H), 1.50 (q, J=11.82 Hz, 2H), 1.70-1.78 (m, 1H), 1.83 (br d,J=9.30 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.25 (s, 3H), 2.45-2.49 (m,1H), 3.29 (dd, J=8.10, 13.10 Hz, 1H), 3.77 (s, 3H), 4.18 (dd, J=2.04,13.10 Hz, 1H), 4.37 (br t, J=8.10 Hz, 1H), 6.85 (br d, J=6.36 Hz, 1H),6.92 (d, J=6.36 Hz, 1H), 7.20 (s, 1H), 7.24 (dd, J=1.26, 8.51 Hz, 1H),7.30 (d, J=7.88 Hz, 2H), 7.56-7.60 (m, 3H), 7.70 (s, 1H), 9.37 (s, 1H),12.14 (br s, 1H); MS (ESI) [M+1]⁺ 529.

Example C-89:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.95 (t, J=7.10 Hz, 3H), 1.13 (q,J=12.13 Hz, 2H), 1.49 (q, J=12.13 Hz, 2H), 1.51-1.78 (m, 5H), 1.84 (brd, J=10.10 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 1H), 3.47(dd, J=13.40, 7.41 Hz, 1H), 4.03 (d, J=11.35 Hz, 1H), 4.21-4.27 (m, 1H),7.01 (t, J=7.41 Hz, 1H), 7.15 (s, 1H), 7.16 (d, J=8.83 Hz, 1H),7.27-7.31 (m, 4H), 7.49 (d, J=8.20 Hz, 2H), 7.52-7.57 (m, 3H), 9.16 (s,1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 513.

Example C-90:2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (t, J=7.09 Hz, 3H), 1.07-1.16 (m,2H), 1.15 (t, J=7.09 Hz, 3H), 1.49 (q, J=11.03 Hz, 2H), 1.49-1.78 (m,5H), 1.83 (br d, J=10.09 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.49 (m,1H), 2.60 (q, J=7.46 Hz, 2H), 3.53 (dd, J=13.56, 6.94 Hz, 1H), 4.03 (d,J=12.61 Hz, 1H), 4.23-4.29 (m, 1H), 7.14-7.20 (m, 4H), 7.25 (d, J=7.57Hz, 1H), 7.29 (d, J=8.04 Hz, 3H), 7.55 (d, J=7.57 Hz, 2H), 7.65 (d,J=8.51 Hz, 1H), 8.57 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 541.

Example C-91:2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (t, J=7.09 Hz, 3H), 1.13 (q,J=11.50 Hz, 2H), 1.44-1.64 (m, 5H), 1.65-1.78 (m, 2H), 1.83 (br d,J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.44-2.49 (m, 1H), 3.49 (dd,J=13.56, 6.94 Hz, 1H), 4.06 (d, J=12.61 Hz, 1H), 4.21-4.27 (m, 1H), 7.16(s, 1H), 7.17 (d, J=9.50 Hz, 1H), 7.29 (d, J=7.57 Hz, 2H), 7.54-7.60 (m,4H), 7.62-7.67 (m, 2H), 8.82 (s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]⁺599.

Example C-92:2-((1r,4r)-4-(4-(3-methyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.66 Hz, 2H), 1.21 (d,J=6.62 Hz, 3H), 1.49 (q, J=11.66 Hz, 2H), 1.79-1.78 (br s, 1H),1.78-1.87 (m, 4H), 2.14 (d, J=6.31 Hz, 2H), 2.38-2.49 (m, 1H), 4.13 (d,J=10.40 Hz, 1H), 4.27 (d, J=10.4 Hz, 1H), 4.57 (br d, J=6.62 Hz, 1H),7.00 (t, J=7.25 Hz, 1H), 7.14-7.22 (m, 2H), 7.24-7.34 (m, 4H), 7.47 (d,J=9.12 Hz, 1H), 7.51 (d, J=8.20 Hz, 2H), 7.55 (d, J=7.74 Hz, 2H), 9.14(s, 1H); MS (ESI) [M+1]⁺ 485.

Example C-93:2-((1r,4r)-4-(4-(2-ethyl-4-(2-ethylphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.05 (t, J=7.41 Hz, 4H), 1.16 (t, J=7.41Hz, 4H), 1.49 (dd, J=12.50, 2.00 Hz, 2H), 1.65-1.79 (m, 3H), 1.83 (d,J=9.77 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.60 (q, J=7.57 Hz, 2H), 3.33(br s, 1H), 3.50 (dd, J=13.56, 7.25 Hz, 1H), 4.07 (d, J=11.66 Hz, 1H),4.17 (d, J=6.62 Hz, 1H), 7.14-7.21 (m, 4H), 7.24-7.32 (m, 4H), 7.55 (d,J=8.20 Hz, 2H), 7.66 (d, J=9.14 Hz, 1H), 8.56 (s, 1H); MS (ESI) [M+1]⁺527.

Example C-94:2-((1r,4r)-4-(4-(2-ethyl-4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆)

ppm 1.04 (t, J=7.41 Hz, 3H), 1.09-1.18 (m, 2H), 1.45-1.54 (m, 2H),1.63-1.78 (m, 3H), 1.83 (d, J=9.46 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H),2.47 (m, 1H), 3.48 (dd, J=13.40, 7.41 Hz, 1H), 4.09 (d, J=11.98 Hz, 1H),4.12-4.18 (m, 1H), 7.15-7.22 (m, 2H), 7.29 (d, J=8.20 Hz, 2H), 7.56 (d,J=7.88 Hz, 2H), 7.59 (d, J=6.62 Hz, 2H), 7.65 (dd, J=8.51, 5.99 Hz, 2H),8.82 (br s, 1H), 12.11 (br s, 1H); MS (ESI) [M+1]⁺ 585.

Example C-95:2-((1r,4r)-4-(4-(2-ethyl-4-(2-methoxyphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆)

ppm 1.03 (t, J=7.41 Hz, 3H), 1.09-1.19 (m, 2H), 1.45-1.55 (m, 2H),1.63-1.79 (m, 3H), 1.84 (br d, J=10.50 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H),2.48 (m, 1H), 3.33 (br s, 2H), 3.40 (dd, J=13.87, 7.88 Hz, 1H), 3.81 (s,3H), 4.13-4.20 (m, 1H), 6.92-6.96 (m, 1H), 7.03-7.08 (m, 2H), 7.21 (s,1H), 7.24 (dd, J=7.24, 2.00, 1H), 7.30 (d, J=7.88 Hz, 2H), 7.57-7.62 (m,3H), 7.87 (d, J=7.88 Hz, 1H), 8.30 (s, 1H), 12.06 (br s, 1H); MS (ESI)[M+1]⁺ 529.

Example C-96:2-((1r,4r)-4-(4-(4-(benzylsulfonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (t, J=7.41 Hz, 3H), 1.14 (qd,J=12.50, 2.50 Hz, 2H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.58-1.65 (m,2H), 1.71-1.79 (m, 1H), 1.83 (br d, J=9.00 Hz, 4H), 2.16 (d, J=6.94 Hz,2H), 2.46-2.50 (m, 1H), 3.09 (dd, J=13.56, 8.83 Hz, 1H), 3.33 (br s,1H), 3.85 (m, 1H), 3.91 (d, J=14.00 Hz, 1H), 4.72 (d, J=14.00 Hz, 1H),4.80 (d, J=14.00 Hz, 1H), 7.12 (dd, J=8.50, 2.00 Hz, 1H), 7.15 (d,J=2.00 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H),7.34-7.42 (m, 5H), 7.55 (d, J=8.20 Hz, 2H); MS (ESI) [M+1]⁺ 534

Example C-97:2-((1r,4r)-4-(4-(2-ethyl-4-(2-(trifluoromethyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.16 (t, J=7.25 Hz, 3H), 1.27 (q,J=12.50 Hz, 2H), 1.62 (q, J=12.50 Hz, 2H), 1.71-1.88 (m, 2H), 1.90-1.98(br m, 2H), 2.02 (d, J=12.50 Hz), 2.38 (d, J=6.62 Hz, 2H), 2.59 (t,J=11.98 Hz, 1H), 3.36 (dd, J=13.24, 8.20 Hz, 1H), 4.23 (br d, J=5.99 Hz,1H), 4.47 (d, J=12.30 Hz, 1H), 7.21-7.27 (m, 2H), 7.29 (s, 1H),7.30-7.37 (m, 3H), 7.44 (d, J=8.00 Hz, 1H), 7.59 (d, J=8.00 Hz, 1H),7.63 (d, J=8.00 Hz, 2H), 7.79 (br s, 1H), 8.25 (d, J=8.20 Hz, 1H); MS(ESI) [M+1]⁺ 567.

Example C-98:2-((1r,4r)-4-(4-(2-ethyl-4-(2-phenylacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.94 (t, J=7.09 Hz, 3H),1.14 (q, J=11.75Hz, 2H), 1.49 (q, J=11.75 Hz, 2H), 1.55-1.65 (m, 2H), 1.69-1.78 (br s,1H), 1.78-1.87 (br s, 4H), 2.15 (d, J=6.62 Hz, 2H), 2.46-2.50 (m, 1H),3.28-3.41 (m, 4H), 3.98 (d, J=15.45 Hz, 1H), 4.06 (d, J=15.76 Hz, 1H),4.22 (d, J=10.40 Hz, 1H), 7.13-7.22 (m, 2H), 7.23-7.36 (m, 7H), 7.56 (d,J=7.57 Hz, 2H), 12.11 (br s, 1H); MS (ESI) [M+1]⁺ 498.

Example C-99:2-((1r,4r)-4-(4-(2-ethyl-4-(2-propylphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.90 (t, J=7.41 Hz, 3H), 1.05 (t, J=7.41Hz, 3H), 1.09-1.18 (m, 2H), 1.45-1.59 (m, 4H), 1.64-1.80 (m, 3H), 1.83(d, J=9.77 Hz, 4H), 2.16 (d, J=7.25 Hz, 2H), 2.44-2.57 (m, 1H), 3.51(dd, J=13.40, 7.09 Hz, 1H), 4.07 (dd, J=13.40, 2.00 Hz, 1H), 4.17 (qd,J=7.09, 2.00 Hz, 1H), 7.12-7.24 (m, 5H), 7.29 (d, J=8.20 Hz, 2H), 7.33(d, J=8.20 Hz, 1H), 7.55 (d, J=8.20 Hz, 2H), 7.64 (d, J=8.20 Hz, 2H),8.52 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺ 541.

Example C-100:2-((1r,4r)-4-(4-(4-(3,5-difluorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.14 (q,J=12.00 Hz, 2H), 1.45 (q, J=12.00 Hz, 2H), 1.63-1.78 (m, 2H), 1.84 (brd, J=10.00 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.46-2.51 (m, 1H), 3.48(dd, J=13.40, 7.41 Hz, 1H), 4.04 (dd, J=13.50, 2.50 Hz, 1H), 4.14-4.22(m, 1H), 6.84 (tt, J=9.30, 2.21 Hz, 1H), 7.14-7.15 (m, 2H), 7.26 (dd,J=9.30, 2.21 Hz, 2H), 7.30 (d, J=8.00 Hz, 2H), 7.51 (d, J=9.00 Hz, 1H),7.56 (d, J=8.00 Hz, 2H), 9.56 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺535.

Example C-101:2-((1r,4r)-4-(4-(4-(3,4-difluorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.14 (q,J=11.83 Hz, 2H), 1.49 (q, J=11.83 Hz, 2H), 1.63-1.78 (m, 2H), 1.84 (brd, J=10.5 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.48 (dd,J=13.40, 7.41 Hz, 1H), 4.04 (d, J=13.40 Hz, 1H), 4.17 (q, J=7.41 Hz,1H), 6.84 (td, J=9.30, 2.21 Hz, 3H), 7.14-7.20 (m, 2H), 7.25-7.31 (m,3H), 7.36 (q, J=9.83 Hz, 1H), 7.58-7.52 (m, 3H), 7.63 (qd, J=7.50, 2.50Hz, 1H), 9.56 (s, 1H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺ 535.

Example C-102:2-((1r,4r)-4-(4-(4-(4-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.13 (q,J=12.17 Hz, 2H), 1.49 (q, J=12.17 Hz, 2H), 1.60-1.75 (m, 3H), 1.83 (brd, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.54 (m, 1H), 3.48(dd, J=13.40, 7.41 Hz, 1H), 4.04 (d, J=13.40 Hz, 1H), 4.17 (q, J=7.41Hz, 1H), 7.15-7.18 (m, 2H), 7.29 (d, J=8.50 Hz, 2H), 7.35 (d, J=8.50 Hz,2H), 7.54 (t, J=8.50 Hz, 5H), 9.31 (s, 3H); MS (ESI) [M+1]⁺ 533.

Example C-103:2-((1r,4r)-4-(4-(4-(3-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.14 (qd,J=12.50, 2.50 Hz, 2H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.63-1.78 (m,3H), 1.83 (br d, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.50 (m,1H), 3.48 (dd, J=13.56, 7.25 Hz, 1H), 4.04 (dd, J=13.40, 2.36 Hz, 1H),4.17 (qd, J=7.00, 2.50 Hz, 1H), 7.17-7.22 (m, 3H), 7.29 (d, J=8.00 Hz,2H), 7.33 (t, J=8.00 Hz, 1H), 7.50 (d, J=8.00 Hz, 1H), 7.56 (d, J=8.00Hz, 1H), 7.67 (d, J=8.00 Hz, 1H), 7.69 (d, J=8.00 Hz, 1H), 9.37 (s, 1H),12.08 (br s, 1H); MS (ESI) [M+1]⁺ 533.

Example C-104:2-((1r,4r)-4-(4-(2-ethyl-4-(4-methoxyphenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.41 Hz, 3H), 1.13 (q,J=11.50 Hz, 2H), 1.49 (q, J=11.50 Hz, 2H), 1.60-1.75 (m, 3H), 1.83 (brd, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.56 (m, 1H) 3.45 (dd,J=13.25, 6.80 Hz, 1H), 3.73 (s, 3H), 4.03 (d, J=13.50 Hz, 1H), 4.14 (q,J=6.80 Hz, 1H), 6.88 (d, J=8.83 Hz, 2H), 7.13-7.18 (m, 2H), 7.29 (d,J=7.88 Hz, 2H), 7.40 (d, J=8.83 Hz, 2H), 7.53-7.58 (m, 3H), 8.99 (s, 1H)12.24 (br s, 1H); MS (ESI) [M+1]⁺ 529.

Example C-105:2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=12.00 Hz, 2H), 1.37 (d,J=6.31 Hz, 3H), 1.49 (q, J=12.00 Hz, 2H), 1.70-1.80 (m, 2H) 1.83 (br d,J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.52 (m, 1H), 3.38 (dd,J=13.56, 7.57 Hz, 1H), 4.15 (dd, J=13.24, 2.21 Hz, 1H), 4.37-4.44 (m,1H), 7.15-7.21 (m, 3H), 7.29 (d, J=8.00 Hz, 2H), 7.34 (t, J=7.50 Hz,1H), 7.50 (d, J=8.00 Hz, 1H), 7.56 (d, J=8.00 Hz, 2H), 7.66 (d, J=8.00Hz, 1H), 7.71 (d, J=8.00 Hz, 1H), 8.78 (s, 1H), 12.14 (br s, 1H); MS(ESI) [M+1]⁺ 519.

Example C-106:2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=12.50 Hz, 2H),1.17 (d, J=3.00Hz, 3H) 1.19 (d, J=3.00 Hz, 3H),1.37 (d, J=5.99 Hz, 3H), 1.49 (q,J=12.50 Hz, 2H), 1.71-1.79 (m, 1H), 1.83 (d, J=9.77 Hz, 4H), 2.15 (d,J=6.94 Hz, 2H), 2.46-2.50 (m, 1H), 3.14-3.19 (m, 1H), 3.44 (dd, J=13.40,7.41 Hz, 1H), 4.08 (dd, J=13.24, 2.21 Hz, 1H), 4.37-4.43 (m, 1H),7.14-7.25 (m, 3H), 7.23 (t, J=7.88 Hz, 2H), 7.29 (d, J=8.50 Hz, 2H),7.33 (d, J=7.50 Hz, 1H), 7.55 (d, J=7.88 Hz, 2H), 7.67 (d, J=8.51 Hz,1H), 8.57 (s, 2H), 12.14 (br s, 1H); MS (ESI) [M+1]⁺ 527.

Example C-107:2-((1r,4r)-4-(4-(4-(sec-butylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87 (t, J=7.50 Hz, 3H), 0.89 (t, J=7.50Hz, 3H), 1.11 (t, J=6.50 Hz, 6H), 1.07-1.18 (m, 4H), 1.30 (d, J=6.50 Hz,3H), 1.32 (d, J=6.50 Hz, 3H), 1.38-1.55 (m, 8H), 1.71-1.79 (m, 2H),1.80-1.86 (m, 8H), 2.15 (d, J=6.94 Hz, 4H), 2.45-2.54 (m, 1H), 3.20 (dd,J=13.40, 8.04 Hz, 1H), 3.30 (dd, J=13.75, 7.75 Hz, 1H), 3.60-3.70 (m,2H), 3.90 (dd, J=13.24, 2.52 Hz, 1H), 3.99 (dd, J=13.40, 2.36 Hz, 1H),4.19-4.30 (m, 2H), 6.64 (d, J=8.00 Hz, 1H), 6.65 (d, J=8.00 Hz, 1H),7.08-7.17 (m, 4H), 7.28 (d, J=8.20 Hz, 4H), 7.53 (d, J=7.57 Hz, 4H),7.60 (d, J=8.50 Hz, 1H), 7.17 (d, J=8.50 Hz, 1H), 12.08 (br s, 1H); MS(ESI) [M+1]⁺ 465.

Example C-108:2-((1r,4r)-4-(4-(4-(cyclohexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.50 Hz, 2H), 1.20-1.33 (m,2H), 1.30 (d, J=6.50 Hz, 3H), 1.49 (q, J=12.50 Hz, 2H), 1.59 (br d,J=13.00 Hz, 1H), 1.59 (d, J=12.30 Hz, 2H), 1.68-1.78 (m, 2H), 1.80-1.86(m, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 2H), 3.22 (dd, J=13.50,8.00 Hz, 1H), 3.47-3.54 (m, 1H), 3.95 (dd, J=13.24, 2.21 Hz, 1H),4.21-4.27 (m, 1H), 6.69 (d, J=7.57 Hz, 1H), 7.09 (d, J=2.00 Hz, 1H),7.12 (dd, J=8.50, 2.50 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H), 7.53 (d, J=8.20Hz, 2H), 7.61 (d, J=8.20 Hz, 1H); MS (ESI) [M+1]⁺ 491.

Example C-109:2-((1r,4r)-4-(4-(2-methyl-4-(2-(trifluoromethoxy)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (qd, J=12.50, 3.00 Hz, 2H), 1.35(d, J=5.99 Hz, 3H), 1.49 (qd, J=12.50, 3.00 Hz, 2H), 1.74 (td, J=7.41,3.78 Hz, 1H), 1.84 (br d, J=10.00 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H),2.46-2.50 (m, 1H), 3.41 (dd, J=13.56, 7.57 Hz, 1H), 4.10 (dd, J=13.40,2.36 Hz, 1H), 4.36-4.41 (m, 1H), 7.15-7.19 (m, 2H), 7.26 (qd, J=8.00,1.42 Hz, 1H), 7.30 (d, J=8.00 Hz, 2H), 7.36-7.41 (m, 2H), 7.55 (d,J=6.50 Hz, 2H), 7.59 (d, J=9.50 Hz, 1H), 7.69 (dd, J=8.04, 1.42 Hz, 3H),8.89 (s, 1H),12.14 (br s, 1H); MS (ESI) [M+1]⁺ 569.

Example C-110:2-((1r,4r)-4-(4-(2-methyl-4-(4-(trifluoromethoxy)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (qd, J=12.50, 2.50 Hz, 2H), 1.36(d, J=6.00 Hz, 3H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.71-1.79 (m, 1H),1.83 (br d, J=9.77 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.46-2.50 (m, 1H),3.37 (dd, J=13.25, 7.75 Hz, 1H), 4.10 (dd, J=13.25, 1.75 Hz, 1H),4.34-4.40 (m, 1H), 7.15-7.18 (m, 2H), 7.30 (t, J=8.20 Hz, 4H), 7.53-7.58(m, 3H), 7.61 (d, J=9.00 Hz, 2H), 9.38 (s, 1H), 12.08 (br s, 1H); MS(ESI) [M+1]⁺ 569.

Example C-111:2-((1r,4r)-4-(4-(4-(2-chlorophenylcarbamoyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.04 (t, J=7.41 Hz, 3H), 1.14 (qd,J=12.50, 2.50 Hz, 2H), 1.49 (qd, J=12.50, 2.50 Hz, 2H), 1.63-1.79 (m,3H), 1.83 (br d, J=9.50 Hz, 4H), 2.15 (d, J=7.00 Hz, 2H), 2.45-2.55 (m,1H), 3.48 (dd, J=13.75, 7.25 Hz, 1H), 4.12 (dd, J=13.50, 2.50 Hz, 1H),4.15-4.23 (m, 1H), 7.17-7.21 (m, 3H), 7.29 (d, J=8.00 Hz, 2H), 7.34 (t,J=8.00 Hz, 1H), 7.50 (d, J=7.88 Hz, 1H), 7.56 (d, J=7.88 Hz, 2H), 7.67(d, J=8.20 Hz, 1H), 7.69 (d, J=8.20 Hz, 1H), 8.78 (s, 1H) 12.08 (br s,1H); MS (ESI) [M+1]⁺ 533.

Example C-112:2-((1r,4r)-4-(4-(4-(benzylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (qd, J=12.75, 3.00 Hz, 2H), 1.32(d, J=6.00 Hz, 3H), 1.49 (qd, J=12.75, 3.00 Hz, 2H),1.72-1.78 (m,1H),1.80-1.88 (m, 1H), 2.15 (d, J=6.94 Hz, 2H), 2.44-2.54 (m, 1H), 3.26(dd, J=13.56, 7.88 Hz, 1H), 4.05 (dd, J=13.40, 2.36 Hz, 1H), 4.25-4.31(m, 1H), 4.34 (d, J=5.50 Hz, 2H), 7.12 (d, J=2.00 Hz, 1H), 7.14 (dd,J=8.50, 2.50 Hz, 1H), 7.23-7.26 (m, 1H), 7.28 (d, J=8.50 Hz, 2H),7.30-7.36 (m, 4H), 7.53 (d, J=8.00 Hz, 2H), 7.56 (t, J=11.50 Hz, 1H),7.66 (d, J=8.51 Hz, 1H), 12.11 (br s, 1H); MS (ESI) [M+1]⁺ 499.

Example C-113:2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d_(s)) δ ppm 0.86 (t, J=6.75 Hz, 3H), 1.13 (br q,J=12.25 Hz, 2H), 1.26-1.33 (m, 8H), 1.44-1.53 (m, 4H),1.70-1.80 (m, 1H),1.83 (br d, J=9.50 Hz, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.50 (m, 1H),3.07-3.14 (m, 2H), 3.21 (dd, J=13.40, 8.04 Hz, 1H), 3.97 (dd, J=13.40,2.36 Hz, 1H), 4.21-4.27 (m, 1H), 6.95 (t, J=5.52 Hz, 1H), 7.10 (d,J=2.50 Hz, 1H), 7.13 (dd, J=8.50, 2.50 Hz, 1H), 7.28 (d, J=8.20 Hz, 2H),7.53 (d, J=8.51 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 12.08 (br s, 1H); MS(ESI) [M+1]⁺ 493.

Example C-114:2-((1r,4r)-4-(4-(2-methyl-4-(pyridazin-4-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (d, J=11.33 Hz, 2H), 1.37 (d,J=6.00 Hz, 3H), 1.49 (d, J=11.33 Hz, 2H), 1.70-1.79 (m, 1H), 1.83 (br d,J=9.00 Hz, 4H), 2.16 (d, J=6.50 Hz, 2H), 3.44 (dd, J=13.24, 7.88 Hz,1H), 4.20 (d, J=13.50 Hz, 1H), 4.37-4.47 (m, 1H), 7.19 (br s, 2H), 7.30(d, J=8.20 Hz, 2H), 7.57 (d, J=7.88 Hz, 2H), 7.63 (d, J=8.83 Hz, 1H),7.96-8.00 (m, 1H), 9.10 (d, J=5.99 Hz, 1H), 9.35 (d, J=2.00 Hz, 1H),12.01 (br s, 1H); MS (ESI) [M+1]⁺ 487.

Example C-115:2-((1r,4r)-4-(4-(2-methyl-4-(phenethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (bq, J=12.50 Hz, 2H), 1.29 (d,J=6.31 Hz, 3H), 1.49 (bq, J=12.50 Hz, 2H),1.72-1.78 (m, 1H), 1.77-1.87(m, 4H), 2.16 (d, J=6.50 Hz, 2H), 2.81 (t, J=6.78 Hz, 2H), 3.16 (dd,J=13.56, 7.88 Hz, 1H), 3.29-3.41 (m, 4H), 3.95 (dd, J=13.40, 2.36 Hz,1H), 4.17-4.23 (m, 1H), 7.01 (m, J=5.50 Hz, 1H), 7.08 (d, J=2.00 Hz,1H), 7.20-7.26 (m, 3H), 7.29 (d, J=8.00 Hz, 2H), 7.32 (t, J=7.50 Hz,2H), 7.47 (d, J=8.83 Hz, 1H), 7.53 (d, J=8.20 Hz, 2H), 12.03 (br s, 1H);MS (ESI) [M+1]⁺ 513.

Example C-116:2-((1r,4r)-4-(4-(4-(heptylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88 (t, J=6.75 Hz, 3H), 1.14 (qd,J=12.50, 2.50 Hz, 2H), 1.24-1.32 (m, 10H), 1.44-1.53 (m, 4H), 1.71-1.80(m, 1H), 1.83 (br d, J=9.46 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.45-2.54(m, 1H), 3.07-3.14 (m, 2H), 3.21 (dd, J=13.40, 7.72 Hz, 1H), 3.97 (dd,J=13.40, 2.36 Hz, 1H), 4.21-4.27 (m, 1H), 6.94 (t, J=5.36 Hz, 1H), 7.10(d, J=2.00 Hz, 1H), 7.13 (dd, J=8.75, 1.75 Hz, 1H), 7.28 (d, J=8.20 Hz,2H), 7.53 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 12.03 (br s, 1H);MS (ESI) [M+1]⁺ 507.

Example C-117:2-((1r,4r)-4-(4-(2-methyl-4-(4-methylphenethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (dq, J=12.50, 2.50 Hz, 2H), 1.29(d, J=6.50 Hz, 3H), 1.49 (dq, J=12.50, 2.50 Hz, 2H),1.69-1.78 (m, 1H),1.83 (br d, J=9.46 Hz, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.28 (s, 3H),2.45-2.53 (m, 1H), 2.76 (t, J=7.41 Hz, 2H), 3.16 (dd, J=13.25, 7.75 Hz,1H), 3.26-3.38 (m, 3H), 3.95 (dd, J=8.25, 1.75 Hz, 1H), 4.14-4.2 (m,1H), 6.98 (t, J=5.50 Hz, 1H), 7.07-7.13 (m, 5H), 7.28 (d, J=8.20 Hz,2H), 7.47 (d, J=8.20 Hz, 1H), 7.53 (d, J=8.20 Hz, 2H), 12.04 (br s, 1H);MS (ESI) [M+1]⁺ 527.

Example C-118:2-((1r,4r)-4-(4-(2-methyl-4-(4-phenylbutylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (br q, J=11.50 Hz, 2H), 1.30 (d,J=5.99 Hz, 3H), 1.44-1.54 (m, 4H), 1.56-1.63 (m, 2H), 1.72-1.79 (m, 1H),1.83 (br d, J=9.00 Hz, 4H), 2.16 (d, J=6.62 Hz, 2H), 2.45-2.50 (m, 1H),2.61 (t, J=7.41 Hz, 2H), 3.14 (br s, 3H), 3.21 (dd, J=13.50, 2.75 Hz,1H), 3.96 (d, J=13.00 Hz, 1H), 4.23 (t, J=5.75 Hz, 1H), 6.97 (t, J=5.25Hz, 1H), 7.08-7.14 (m, 2H), 7.18 (t, J=7.50 Hz, 1H), 7.21 (d, J=7.00 Hz,2H), 7.25-7.31 (m, 4H), 7.53 (d, J=7.88 Hz, 2H), 7.59 (d, J=8.20 Hz,1H), 12.04 (br s, 1H); MS (ESI) [M+1]⁺ 541.

Example C-119:2-((1r,4r)-4-(4-(2-methyl-4-(octylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87 (t, J=6.75 Hz, 3H), 1.13 (qd,J=12.33, 2.25 Hz, 2H), 1.20-1.33 (m, 13H), 1.43-1.54 (m, 4H), 1.70-1.79(m, 1H), 1.83 (br d, J=9.50 Hz, 4H), 2.16 (d, J=6.94 Hz, 2H), 2.46-2.52(m, 1H), 3.07-3.14 (m, 2H), 3.21 (dd, J=13.24, 7.88 Hz, 1H), 3.97 (dd,J=13.24, 2.21 Hz, 1H), 4.20-4.28 (m, 1H), 6.94 (t, J=5.36 Hz, 1H), 7.10(d, J=2.00 Hz, 1H), 7.13 (dd, J=8.75, 1.75 Hz, 1H), 7.28 (d, J=8.20 Hz,2H), 7.53 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 12.04 (br s, 1H);MS (ESI) [M+1]⁺ 521.

Example C-120:2-((1r,4r)-4-(4-(4-(decylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.86 (t, J=7.00 Hz, 3H), 1.14 (qd,J=12.13, 2.75 Hz, 2H), 1.20-1.33 (m, 16H), 1.41-1.54 (m, 4H), 1.68-1.78(m, 1H), 1.83 (br d, J=9.50 Hz, 4H) 2.16 (d, J=6.94 Hz, 2H), 3.06-3.14(m, 2H), 3.21 (dd, J=13.24, 7.88 Hz, 1H), 3.97 (dd, J=13.24, 2.21 Hz,1H), 4.20-4.26 (m, 1H), 6.94 (t, J=5.50 Hz, 1H), 7.10 (d, J=2.00 Hz,1H), 7.13 (dd, J=8.50, 2.50 Hz, 1H), 7.28 (d, J=8.00 Hz, 2H), 7.53 (d,J=8.00 Hz, 2H), 7.60 (d, J=8.50 Hz, 1H), 12.04 (br s, 1H); MS (ESI)[M+1]⁺ 549.

Example C-121:2-((1r,4r)-4-(4-(4-(3-ethoxypropylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.08 (t, J=7.00 Hz, 3H), 1.14 (qd,J=12.50, 2.50 Hz, 2H), 1.31 (d, J=6.50 Hz, 3H), 1.49 (qd, J=12.50, 2.50Hz, 2H), 1.67-1.78 (m, 3H), 1.83 (br d, J=9.50 Hz, 4H), 2.16 (d, J=7.00Hz, 2H), 2.46-2.52 (m, 1H), 3.12-3.24 (m, 3H), 3.40 (q, J=13.67 Hz, 4H),3.98 (dd, J=13.25, 2.25 Hz, 1H), 4.20-4.28 (m, 1H), 6.93 (t, J=5.25 Hz,1H), 7.10 (d, J=2.00 Hz, 1H), 7.13 (dd, J=8.50, 2.00 Hz, 1H), 7.28 (d,J=8.00 Hz, 2H), 7.53 (d, J=8.00 Hz, 2H), 7.61 (d, J=8.50 Hz, 1H), 12.03(s, 1H); MS (ESI) [M+1]⁺ 495.

Example C-122:2-((1r,4r)-4-(4-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (qd, J=12.50, 3.00 Hz, 2H), 1.30(d, J=6.50 Hz, 3H), 1.47 (qd, J=12.50, 3.00 Hz, 2H), 1.68-1.78 (m, 1H),1.82 (t, J=10.50 Hz, 4H), 2.15 (d, J=7.00 Hz, 2H), 2.45 (tt, J=12.00,2.92 Hz, 1H), 2.95 (dd, J=11.75, 8.25 Hz, 1H), 3.33 (d, J=2.50 Hz, 1H),3.35 (d, J=3.00 Hz, 1H), 4.07-4.18 (m, 1H), 5.88 (s, 1H), 6.62 (d,J=8.00 Hz, 1H), 6.93 (d, J=2.00 Hz, 1H), 6.97 (dd, J=8.00, 2.00 Hz, 1H),7.22 (d, J=8.50 Hz, 2H), 7.43 (d, J=8.50 Hz, 2H),12.06 (br s, 1H); MS(ESI) [M+1]⁺ 495.

Example C-123: methyl2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)acetate

¹H NMR (500 MHz, CDCl₃) δ ppm 1.28-1.35 (m, 4H), 1.31 (d, J=7.0 Hz, 6H),1.59 (q, J=10.0 Hz, 1H), 1.71 (s, 1H), 1.93-2.00 (m, 3H), 2.29 (d, J=6.5Hz, 2H), 2.57 (m, 1H), 2.82 (s, 3H), 3.13 (m, 1H), 3.72 (s, 3H), 7.29(s, 1H), 7.32-7.42 (m, 3H), 7.47 (s, 1H), 7.76 (m, 3H), 7.85 (d, J=9.0Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 8.30-8.32 (m, 2H); MS (ESI) [M+1]⁺ 535.

Example C-124:7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)quinoline-4-carboxylicacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=12.5 Hz, 2H), 1.54 (q, J=12.5Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.50 (m, 1H), 7.42(d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.93 (d, J=5.0 Hz, 1H), 8.08(d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.79 (d, J=9.0 Hz, 1H), 9.07 (s, 1H),12.06 (s, 1H), 13.90 (br s, 1H); MS (ESI) [M+1]⁺ 390.

Example C-125:2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=12.5 Hz, 2H), 1.23 (d, J=6.5Hz, 6H), 1.54 (q, J=12.5 Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d, J=7.0 Hz,2H), 2.54 (m, 1H), 3.28-3.85 (m, 1H), 7.35 (d, J=7.5 Hz, 2H), 7.43 (d,J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.81-7.84 (m, 4H), 8.13 (d, J=8.5Hz, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 9.15 (d, J=4.5 Hz, 1H),10.40 (s, 1H); MS (ESI) [M+1]⁺ 507.

Example C-126:2-((1r,4r)-4-(4-(4-(pyridin-2-ylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=11.6 Hz, 2H), 1.54 (q, J=11.6Hz, 2H), 1.73-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H),7.23-7.26 (m, 1H), 7.42 (d, J=7.5 Hz, 2H), 7.71 (d, J=4.5 Hz, 1H), 7.81(d, J=8.0 Hz, 2H), 7.93 (t, J=8.0 Hz, 1H), 8.04 (d, J=8.5 Hz, 2H), 8.20(d, J=8.5 Hz, 1H), 8.30-8.35 (m, 1H), 8.42 (d, J=4.0 Hz, 1H), 9.04 (d,J=4.0 Hz, 1H), 11.34 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]⁺ 466.

Example C-127:2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=12.5 Hz, 2H), 1.22 (t, J=6.5Hz, 3H), 1.54 (q, J=12.5 Hz, 2H), 1.71-1.87 (m, 5H), 2.18 (d, J=7.0 Hz,2H), 2.54 (m, 1H), 2.73 (q, J=7.5 Hz, 2H), 7.28-7.30 (m, 2H), 7.42 (d,J=8.0 Hz, 2H), 7.53 (d, J=6.5 Hz, 1H), 7.74 (d, J=3.5 Hz, 1H), 7.83 (d,J=8.5 Hz, 2H), 8.08 (d, J=9.0 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.36 (s,1H), 9.09 (d, J=4.5 Hz, 2H), 10.32 (s, 1H); MS (ESI) [M+1]⁺ 493.

Example C-128:2-((1r,4r)-4-(4-(4-(2,4-difluorophenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=12.0 Hz, 2H), 1.53 (q, J=12.0Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 7.22(d, J=9.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 3H), 7.74 (d, J=4.5 Hz, 1H), 7.82(d, J=8.5 Hz, 2H), 8.07 (d, J=7.5 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.35(s, 1H), 9.07 (d, J=4.5 Hz, 1H), 10.66 (s, 1H); MS (ESI) [M+1]⁺ 501.

Example C-129:2-((1r,4r)-4-(4-(4-(2-propylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.95 (t, J=7.0 Hz, 3H), 1.17 (q, J=12.5Hz, 2H), 1.54 (q, J=12.5 Hz, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.71-1.87 (m,5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 2.67 (t, J=7.5 Hz, 2H),7.27-7.34 (m, 2H), 7.42 (d, J=7.5 Hz, 2H), 7.52 (d, J=6.5 Hz, 1H), 7.72(d, J=4.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 8.08 (d, J=8.5 Hz, 1H), 8.29(d, J=9.0 Hz, 1H), 8.37 (s, 1H), 9.10 (d, J=4.0 Hz, 2H), 10.34 (s, 1H);MS (ESI) [M+1]⁺ 507.

Example C-130:2-((1r,4r)-4-(4-(4-(4-fluoro-2-methylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=10.0 Hz, 2H), 1.54 (q, J=12.0Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d, J=6.5 Hz, 2H), 2.35 (s, 3H), 2.54(m, 1H), 7.11-7.15 (m, 2H), 7.22 (d, J=9.5 Hz, 1H), 7.42 (d, J=8.5 Hz,2H), 7.56 (dd, J=8.5, 7.0 Hz, 1H), 7.81-7.84 (m, 2H), 8.09 (d, J=8.5 Hz,1H), 8.32 (d, J=9.0 Hz, 1H), 8.38 (s, 1H), 9.11 (d, J=4.0 Hz, 1H), 10.35(s, 1H); MS (ESI) [M+1]⁺ 497.

Example C-131:2-((1s,4s)-4-(4-(4-(2-isopropylphenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=12.0 Hz, 2H), 1.19 (d, J=5.5Hz, 6H), 1.54 (q, J=12.0 Hz, 2H), 1.76-1.87 (m, 5H), 2.17 (d, J=7.5 Hz,2H), 2.54 (m, 1H), 2.88-2.91 (m, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.42 (d,J=7.5 Hz, 2H), 7.70-7.73 (m, 3H), 7.82 (d, J=8.0 Hz, 2H), 8.04 (d, J=8.5Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 9.07 (d, J=4.5 Hz, 1H),10.73 (s, 1H); MS (ESI) [M+1]⁺ 507.

Example C-132:2-((1s,4s)-4-(4-(5-(2-ethylphenylcarbamoyl)naphthalen-2-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.23 (t, J=5.5Hz, 3H), 1.53 (q, J=11.6 Hz, 2H), 1.69-1.87 (m, 5H), 2.17 (d, J=8.0 Hz,2H), 2.54 (m, 1H), 2.64 (t, J=7.5 Hz, 2H), 6.55 (s, 1H), 7.28-7.32 (m,2H), 7.39-7.40 (m, 3H), 7.60-7.67 (m, 3H), 7.77-7.83 (m, 3H), 8.08-8.36(m, 2H), 10.15 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]⁺ 492.

Example C-133:2-((1r,4r)-4-(4-(5-(2-isopropylphenylcarbamoyl)naphthalen-2-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.22 (d, J=3.0Hz, 6H), 1.56 (q, J=11.6 Hz, 2H), 1.52-1.87 (m, 5H), 2.17 (d, J=7.0 Hz,2H), 2.54 (m, 1H), 2.72-2.77 (m, 1H), 6.55 (s, 2H), 7.26-7.52 (m, 2H),7.60-7.65 (m, 3H), 7.77-7.79 (m, 2H), 8.08-8.15 (m, 2H), 8.31-8.37 (m,2H), 10.09 (s, 1H),10.14 (s, 1H), 12.06 (br s, 1H); MS (ESI) [M+1]⁺ 506

Example C-134:2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.5 Hz, 2H), 1.53 (q, J=11.5Hz, 2H), 1.73-1.87 (m, 5H), 2.17 (d, J=7.0 Hz, 2H), 2.54 (m, 1H), 2.75(s, 3H), 7.17 (t, J=7.5 Hz, 1H), 7.41 (t, J=7.5 Hz, 4H), 7.63 (s, 2H),7.80 (t, J=7.0 Hz, 3H), 7.95 (d, J=9.0 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H),8.25 (s, 1H), 10.78 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 479.

Example C-135:2-((1r,4r)-4-(4-(4-(2-isopropylphenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=10.5 Hz, 2H), 1.23 (d, J=7.0Hz, 6H), 1.54 (q, J=10.5 Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=7.0 Hz,2H), 2.54 (m, 1H), 2.81 (s, 3H), 3.27-3.33 (m, 1H), 7.28-7.35 (m, 2H),7.42-7.46 (m, 2H), 7.72 (s, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.96 (s, 1H),8.04 (d, J=9.0 Hz, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.29 (s, 1H), 10.34 (brs, 1H); MS (ESI) [M+1]⁺ 521.

Example C-136:2-((1r,4r)-4-(4-(4-(2-ethylphenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (q, J=10.5 Hz, 2H), 1.22 (t, J=8.0Hz, 3H), 1.47 (q, J=10.5 Hz, 2H), 1.76-1.87 (m, 5H), 2.08 (s, 2H), 2.54(m, 1H), 2.69-2.75 (m, 2H), 2.77 (s, 3H), 7.27-7.30 (m, 2H), 7.39 (d,J=8.0 Hz, 2H), 7.50 (d, J=9.0 Hz, 2H), 7.63 (s, 1H), 7.79 (d, J=8.0 Hz,2H), 7.97 (d, J=7.0 Hz, 1H), 8.21-8.25 (m, 2H), 10.34 (br s, 1H); MS(ESI) [M+1]⁺ 507.

Example C-137:2-((1r,4r)-4-(4-(4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.04 (q, J=10.5 Hz, 2H), 1.48 (q, J=10.5Hz, 2H), 1.76-1.87 (m, 5H), 1.91 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 2.75(s, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.59 (s, 1H), 7.65-7.72 (m, 2H), 7.79(d, J=7.5 Hz, 2H), 7.83-7.86 (m, 1H), 7.94 (d, J=8.5 Hz, 1H), 8.23 (s,1H), 8.31 (d, J=8.5 Hz, 1H); MS (ESI) [M+1]⁺ 565.

Example C-138:2-((1r,4r)-4-(4-(4-(benzylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=11.6 Hz, 2H), 1.52 (q, J=11.6Hz, 2H), 1.75-1.87 (m, 5H), 2.16 (d, J=7.0 Hz, 2H), 2.51 (m, 1H), 2.77(s, 3H), 4.58 (d, J=6.0 Hz, 2H), 7.29-7.43 (m, 5H), 7.50-7.63 (m, 3H),7.78 (d, J=7.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H),8.28 (br s, 1H), 9.40 (br s, 1H); MS (ESI) [M+1]⁺ 493.

Example C-139:2-((1r,4r)-4-(4-(2-methyl-4-(phenethylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (q, J=10.5 Hz, 2H), 1.53 (q, J=10.5Hz, 2H), 1.75-1.86 (m, 5H), 2.17 (d, J=6.5 Hz, 2H), 2.47 (m, 1H), 2.75(s, 3H), 2.82 (m, 2H), 3.63 (q, J=6.5 Hz, 2H), 7.27-7.37 (m, 5H), 7.43(d, J=7.5 Hz, 2H), 7.47 (s, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.92-7.95 (m,2H), 8.22 (s, 1H), 8.92 (br s, 1H); MS (ESI) [M+1]⁺ 507.

Example C-140:2-((1r,4r)-4-(4-(2-methyl-4-(3-phenylpropylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=10.5 Hz, 2H), 1.52 (q, J=10.5Hz, 2H), 1.56-1.72 (m, 5H), 1.85 (d, J=10.5 Hz, 2H), 2.00-2.22 (m, 3H),2.51 (m, 1H), 2.64-2.68 (m, 1H), 2.70 (s, 3H), 3.86 (m, 2H), 7.18 (m,1H), 7.24-7.31 (m, 4H), 7.39 (d, J=6.0 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H),7.88-7.91 (m, 1H), 8.09-8.12 (m, 1H), 8.17 (s, 1H), 8.19-8.20 (m, 1H),8.77 (m, 1H); MS (ESI) [M+1]⁺ 521.

Example C-141:2-((1r,4r)-4-(4-(2-methyl-4-(4-phenylbutylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q, J=10.5 Hz, 2H), 1.53 (q,J=^(˜)10.5 Hz, 2H), 1.24 (br s, 2H), 1.84-1.91 (m, 5H), 2.17 (d, J=7.0Hz, 2H), 2.37 (m, 2H), 2.44-2.64 (m, 3H), 2.70 (s, 3H), 3.35 (m, 2H),7.21 (t, J=6.0 Hz, 1H), 7.27-7.33 (m, 3H), 7.39 (d, J=8.0 Hz, 1H), 7.42(s, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.92 (d, J=7.0 Hz, 1H), 8.14 (d, J=5.5Hz, 1H), 8.20 (s, 1H), 8.82 (m, 1H), 12.05 (s, 1H); MS (ESI) [M+1]⁺ 535.

Example C-142:2-((1r,4r)-4-(4-(2-methyl-4-(5-phenylpentylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=10.5 Hz, 2H), 1.38-1.44 (m,2H), 1.53 (q, J=10.5 Hz, 2H), 1.54-1.77 (m, 6H), 1.85 (d, J=11.5 Hz,4H), 2.17 (d, J=7.0 Hz, 2H), 2.47-2.55 (m, 1H), 2.62 (t, J=6.5 Hz, 1H),2.69 (s, 3H), 3.35 (m, 2H), 7.17 (t, J=7.0 Hz, 1H), 7.21-7.29 (m, 2H),7.38-7.41 (m, 4H), 7.78 (d, J=8.0 Hz, 2H), 7.90 (d, J=7.0 Hz, 1H), 8.12(d, J=9.0 Hz, 1H), 8.20 (s, 1H), 8.74 (m, 1H), 12.04 (br s, 1H); MS(ESI) [M+1]⁺ 549.

Example C-143:2-((1r,4r)-4-(4-(2-methyl-4-(6-phenylhexylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) ppm 1.54-1.75 (m, 8H), 1.85 (d, J=11.5 Hz,4H), 1.26-1.62 (m, 6H), 2.17 (d, J=7.0 Hz, 2H), 2.47-2.61 (m, 2H), 2.84(s, 3H), 3.36 (m, 2H), 7.15-7.21 (m, 4H), 7.27 (t, J=8.0 Hz, 1H), 7.43(d, J=8.0 Hz, 2H), 7.65 (m, 1H), 7.78 (d, J=7.5 Hz, 1H), 8.05 (m, 1H),8.19 (d, J=9.0 Hz, 1H), 8.33 (s, 1H), 8.90 (brs, 1H); MS (ESI) [M+1]⁺563.

Example C-144:2-((1r,4r)-4-(4-(4-(4H-1,2,4-triazol-4-ylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (q, J=10.5 Hz, 2H), 1.55 (q, J=10.5Hz, 2H), 1.75-1.87 (m, 5H), 2.37 (s, 2H), 2.54 (m, 1H), 2.79 (s, 3H),6.65 (d, J=8.5 Hz, 1H), 7.00 (d, J=7.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H),7.42 (d, J=8.0 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H),8.03 (d, J=9.0 Hz, 1H), 8.30 (s, 1H), 8.35 (d, J=8.50 Hz, 1H), 8.97 (s,1H), 12.60 (br s, 1H); MS (ESI) [M+1]⁺ 470.

Example C-145:2-((1r,4r)-4-(4-(4-(1,3,4-thiadiazol-2-ylcarbamoyl)-2-methylquinolin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (q, J=10.5 Hz, 2H), 1.55 (q, J=10.5Hz, 2H), 1.75-1.87 (m, 5H), 2.17 (d, J=6.0 Hz, 2H), 2.54 (m, 1H), 2.72(s, 3H), 6.55 (s, 1H), 7.26-7.30 (m, 1H), 7.39 (d, J=8.0 Hz, 1H),7.76-7.79 (m, 4H), 7.87 (d, J=8.0 Hz, 1H), 8.18 (s, 1H), 12.60 (br s,1H); MS (ESI) [M+1]⁺ 487.

Example C-146:2-((1r,4r)-4-(4-(1-(pyridin-4-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q,J=11.5 Hz, 2H), 1.52 (q, J=11.6 Hz, 2H), 1.70-1.84 (m, 4H), 1.94 (m,2H), 2.16 (d, J=6.5 Hz, 1H), 2.52-2.56 (m, 1H), 2.82 (t, J=6.5 Hz, 2H),3.17 (m, 2H), 3.74 (t, J=6.0 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.38-7.44(m, 3H), 7.45-7.51 (m, 3H), 7.56 (d, J=8.5 Hz, 2H), 8.36 (br s, 1H),9.38 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 490.

Example C-147:(1R,2R)-2-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzoyl)cyclopentanecarboxylicacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.18 (t, J=7.0 Hz, 1H), 1.56-1.86 (m,2H), 1.97-2.03 (m, 1H), 2.13-2.20 (m, 1H), 2.73 (s, 1H), 2.89 (s, 1H),3.89 (t, J=4.0 Hz, 2H), 4.01-4.13 (m, 1H), 4.32 (t, J=4.0 Hz, 2H), 7.03(t, J=7.5 Hz, 1H), 7.28-7.31 (m, 4H), 7.51 (d, J=8.5 Hz, 2H), 7.66 (d,J=9.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.0 Hz, 2H), 9.21 (brs, 1H); MS (ESI) [M+1]⁺ 471.

Example C-148:(1R,2R)-2-(4-(2-ethyl-4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzoyl)cyclopentanecarboxylicacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (t, J=7.5 Hz, 3H), 1.56-1.86 (m,3H), 1.98-2.05 (m, 1H), 2.14-2.21 (m, 1H), 2.73 (s, 1H), 2.89 (s, 1H),3.24 (q, J=8.0 Hz, 2H), 3.49 (dd, J=7.0 Hz, 1H), 4.04-4.19 (m, 3H), 7.02(t, J=7.0 Hz, 1H), 7.28-7.31 (m, 4H), 7.51 (d, J=8.5 Hz, 2H), 7.62 (d,J=7.5 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H), 8.05 (d, J=8.0 Hz, 2H), 9.22 (brs, 1H), 12.25 (br s, 1H); MS (ESI) [M+1]⁺ 499.

Example C-149:2-((1r,4r)-4-(4-(2-ethyl-4-(3-phenylpropylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.00 (t, J=7.41 Hz, 3H), 1.11 (q,J=11.66 Hz, 2H), 1.43-1.52 (m, 2H), 1.57-1.71 (m, 2H), 1.72-1.87 (m,7H), 2.11 (d, J=6.62 Hz, 2H), 2.44-2.49 (m, 2H), 2.61 (t, J=7.57 Hz,2H), 3.10-3.19 (m, 2H), 3.32 (dd, J=13.40, 7.41 Hz, 1H), 3.93 (d,J=11.66 Hz, 1H), 4.01-4.06 (m, 1H), 7.01 (t, J=5.20 Hz, 1H), 7.10-7.30(m, 9H), 7.53 (d, J=8.20 Hz, 2H), 7.59 (d, J=8.51 Hz, 1H); MS (ESI)[M+1]⁺ 541.

Example C-150:2-((1r,4r)-4-(4-(2-ethyl-4-(heptylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.86-0.88 (m, 3H), 1.00 (t, J=7.41 Hz,3H), 1.08-1.15 (m, 2H), 1.28 (m, 8H), 1.44-1.53 (m, 4H), 1.56-1.64 (m,2H), 1.47 (m, 1H), 1.81-1.84 (m, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.49(m, 2H), 3.06-3.14 (m, 2H), 3.31 (dd, J=7.6, J=13.6, 1H), 3.90-3.92 (m,1H), 4.02 (m, 1H), 6.94-6.96 (m, 1H), 7.12-7.14 (m, 2H), 7.26-7.28 (m,2H), 7.51-7.59 (m, 3H); MS (ESI) [M+1]⁺ 521.

Example C-151:2-((1r,4r)-4-(4-(2-ethyl-4-(hexylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.86-0.88 (m, 3H), 1.00 (t, J=7.41 Hz,3H), 1.08-1.15 (m, 2H), 1.28 (m, 6H), 1.44-1.53 (m, 4H), 1.56-1.64 (m,2H), 1.47 (m, 1H), 1.81-1.84 (m, 4H), 2.15 (d, J=6.94 Hz, 2H), 2.45-2.49(m, 1H), 3.06-3.14 (m, 2H), 3.31 (dd, J=7.6, J=13.6, 1H), 3.90-3.92 (m,1H), 4.02 (m, 1H), 6.94-6.96 (m, 1H), 7.10-7.14 (m, 2H), 7.26-7.28 (m,2H), 7.51-7.59 (m, 3H); MS (ESI) [M+1]⁺ 507.

Example C-152:2-((1r,4r)-4-(4-(4-oxo-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q, J=11.5 Hz, 2H), 1.24 (s, 1H),1.51 (q, J=11.6 Hz, 2H), 1.70-1.93 (m, 3H), 1.82-1.99 (m, 2H), 2.13 (d,J=6.5 Hz, 2H), 2.52-2.56 (m, 1H), 2.82 (t, J=5.5 Hz, 2H), 4.12 (t, J=3.0Hz, 1H), 7.04 (t, J=6.0 Hz, 1H), 7.30-7.35 (m, 2H), 7.52 (d, J=8.0 Hz,2H), 7.58-7.60 (m, 3H), 7.85-7.86 (m, 2H), 8.07 (d, J=2.0 Hz, 2H), 9.55(s, 1H), 12.10 (br s, 1H); MS (ESI) [M+1]⁺ 483.

Example C-153:2-((1r,4r)-4-(4-(4-(tert-butoxycarbonyl)-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ ppm 1.23-1.28 (m, 2H), 1.43 (s, 2H), 1.47 (s,9H), 1.59 (q, J=11.6 Hz, 2H), 1.93-2.11 (m, 3H), 2.35 (d, J=7.0 Hz, 2H),2.54 (m, 1H), 3.42-3.48 (m, 4H), 4.80 (br s, 2H), 7.04-7.07 (m, 3H),7.28-7.35 (m, 5H), 7.56-7.67 (m, 4H); MS (ESI) [M+1]⁺ 584.

Example C-154:2-((1r,4r)-4-(4-(1-(2-hydroxy-2-phenylacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.5 Hz, 2H), 1.48 (q, J=11.6Hz, 2H), 1.70-1.84 (m, 7H), 2.16 (d, J=7.0 Hz, 2H), 2.52-2.56 (m, 1H),2.63-2.70 (m, 2H), 3.16 (s, 1H), 3.64 (m, 2H), 7.30 (d, J=8.5 Hz, 4H),7.39 (s, 2H), 7.45-7.47 (m, 2H), 7.55 (d, J=8.5 Hz, 4H), 12.05 (br s,1H); MS (ESI) [M+1]⁺ 484.

Example C-155:2-((1s,4s)-4-(4-(4-((S)-2-amino-2-phenylacetyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.40 (d, J=6.3Hz, 3H), 1.53 (q, J=11.6 Hz, 2H), 1.75 (m, 1H), 1.83 (d, J=10.5 Hz, 4H),2.16 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 3.32 (m, 1H), 4.15 (br s, 1H),4.36 (s, 1H), 4.69 (s, 1H), 7.31-7.36 (m, 4H), 7.45 (t, J=9.0 Hz, 4H),7.57 (d, J=7.0 Hz, 2H), 7.64 (d, J=7.5 Hz, 2H), 12.04 (br s, 1H); MS(ESI) [M+1]⁺ 499.

Example C-156:2-((1R,4r)-4-(4-(4-((R)-2-amino-2-phenylacetyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.6 Hz, 2H), 1.22 (d, J=6.0Hz, 1H), 1.40 (d, J=6.3 Hz, 3H), 1.48 (q, J=11.6 Hz, 2H), 1.40-1.82 (m,5H), 2.16 (d, J=6.5 Hz, 2H), 2.54 (m, 1H), 3.61 (s, 1H), 4.34 (s, 1H),4.39 (s, 1H), 7.10 (s, 1H), 7.17-7.22 (m, 2H), 7.29 (d, J=8.0 Hz, 3H),7.34-7.42 (m, 4H), 7.54-7.56 (m, 2H), 12.07 (br s, 1H); MS (ESI) [M+1]⁺499.

Example C-157:2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)propanoicacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.06 (d, J=11.5 Hz, 3H), 1.23-1.26 (m,2H), 1.50 (q, J=11.5 Hz, 2H), 1.55-1.61 (m, 4H), 1.73-1.87 (m, 1H),2.16-2.20 (m, 1H), 2.50-2.55 (m, 1H), 3.87 (t, J=4.00 Hz, 2H), 4.30 (t,J=4.0 Hz, 2H), 7.00 (t, J=7.5 Hz, 2H), 7.15-7.17 (m, 2H), 7.28-7.31 (m,3H), 7.50 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.57 (d, J=9.5 Hz,1H), 9.16 s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]⁺ 485.

Section D Preparation of Additional Example Compounds

Example D-1:7-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—stepd1

1-Hydroxybenzotriazole (32.0 mg, 0.25 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.0 mg,0.25 mmol) and2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid C-5 (71.0 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide(2.0 mL). An aqueous ammonium hydroxide solution (0.02 mL, 38% in water)was then added, and the reaction was stirred at room temperature for 2days. The reaction mixture was concentrated under reduced pressure andpurified by flash column chromatography on C₁₈ reverse phase(water:acetonitrile gradient) to give7-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-1 (30.0 mg; Yield=42%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q,J=11.40 Hz, 2H), 1.50 (q, J=11.40 Hz, 2H), 1.70-1.86 (m, 5H), 1.99 (d,J=6.94 Hz, 2H), 2.52-2.55 (m, 1H), 3.86 (t, J=4.10 Hz, 2H), 4.28 (t,J=4.10 Hz, 2H), 7.01 (t, J=7.25 Hz, 1H), 7.16 (s, 4H), 7.26-7.35 (m,4H), 7.46-7.60 (m, 3H), 9.16 (s, 3H); MS (ESI) [M+1]⁺ 470.

Example D-2:7-(4-((1r,4r)-4-(cyanomethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—stepd2

Trifluoroacetic anhydride (20.0 mg, 0.08 mmol) and triethylaluminum(10.0 mg, 0.08 mmol) were successively added to a solution of7-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-1 (40.0 mg, 0.04 mmol) in tetrahydrofuran (3.0 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 40h and concentrated to dryness under reduced pressure. The crude residuewas purified by flash column chromatography on C₁₈ reverse phase(water:acetonitrile gradient) to give7-(4-((1r,4r)-4-(cyanomethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-2 (6.0 mg; Yield=20%). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.91 (q,J=11.35 Hz, 2H), 1.30 (q, J=11.65 Hz, 2H), 1.75 (br s, 1H), 2.01-2.06(m, 4H), 2.37 (d, J=6.50 Hz, 2H), 2.58 (t, J=11.50 Hz, 1H), 2.69 (t,J=5.51 Hz, 2H), 4.00 (t, J=4.50 Hz, 2H), 4.38 (t, J=4.00 Hz, 2H),7.01-7.18 (m, 1H), 7.16-7.39 (m, 5H), 7.48-7.60 (m, 6H); MS (ESI) [M+1]⁺452.

Example D-3:7-(4-((1r,4r)-4-((1H-tetrazol-5-yl)methyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—stepd3

Trimethylaluminum (2 M solution in toluene, 0.50 mL, 1.0 mmol) was addedat 0° C. to a solution of7-(4-((1r,4r)-4-(cyanomethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-2 (80.0 mg, 0.20 mmol) in anhydrous toluene (3.5 mL) under anatmosphere of nitrogen. Azidotrimethylsilane (0.86 mL, 6.5 mmol) wasthen added, and the reaction mixture was heated at 80° C. for 48 h. Thesolution was cooled to room temperature, concentrated to dryness underreduced pressure and the residue was purified by flash columnchromatography on C₁₈ reverse phase (water:acetonitrile gradient) togive7-(4-((1r,4r)-4-((1H-tetrazol-5-yl)methyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-3 (40.0 mg, Yield=60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (q,J=11.4 Hz, 2H), 1.47 (q, J=11.5 Hz, 2H), 1.74-1.83 (m, 3H), 2.50-2.55(m, 1H), 2.82 (d, J=6.5 Hz, 2H), 3.17 (d, J=5.5 Hz, 2H), 3.87 (t, J=4.0Hz, 2H), 4.28 (t, J=4.0 Hz, 2H), 7.00 (t, J=6.5 Hz, 2H), 7.15 (s, 2H),7.27-7.30 (m, 4H), 7.49-7.55 (m, 4H), 9.16 (s, 1H); MS (ESI) [M+1]⁺ 495.

Example D-4:7-(4-((1r,4r)-4-(2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—stepd4

Diisobutylaluminum hydride (1.0 M solution in methylene chloride, 0.08mL, 0.08 mmol) was added under a nitrogen atmosphere to a solution of2-((1r,4r)-4-(4-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid C-5 (40.0 mg, 0.08 mmol) in methylene chloride (10.0 mL) at −78° C.The reaction was allowed to warm up to room temperature overnight andthen quenched with methanol (1.0 mL) and solid sodium sulfatedecahydrate successively. After 60 mins of additional stirring at roomtemperature, the solution was filtered through a celite pad and washedwith ethyl acetate. The combined organic extracts were concentratedunder reduced pressure, and the residue was purified by flash columnchromatography on C₁₈ reverse phase (water:acetonitrile gradient) togive7-(4-((1r,4r)-4-(2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-4 (20.0 mg; Yield=50%). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.92 (q,J=11.35 Hz, 2H), 1.27 (m, 3H), 1.50-1.63 (m, 2H), 1.96-2.04 (m, 2H),2.42 (d, J=6.50 Hz, 2H), 2.58 (t, J=11.00 Hz, 1H), 4.01 (t, J=4.50 Hz,2H), 4.38 (t, J=4.50 Hz, 2H), 7.10 (t, J=7.50 Hz, 1H), 7.19-7.36 (m,6H), 7.39-7.44 (m, 4H), 7.53 (t, J=8.00 Hz, 1H), 9.83 (s, 1H); MS (ESI)[M+1]⁺ 455.

Example D-5:7-(4-((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide—stepd5

A solution of7-(4-((1r,4r)-4-(2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-4 (50.0 mg, 0.1 mmol) in methanol (0.20 mL) was stirred at roomtemperature overnight in the presence of palladium on carbon (10% Pd,2.0 mg) under an atmosphere of hydrogen (balloon). The reaction was thenfiltered through a pad of silica gel and washed with ethyl acetate (3mL). The filtrate was concentrated under reduced pressure, and the cruderesidue was purified by flash column chromatography on silica gel (1:1hexanes:ethyl acetate) to give7-(4-((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamideD-5 (30.0 mg; Yield=60%). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.14 (q,J=11.35 Hz, 2H), 1.27 (br s, 2H), 1.50-1.63 (m, 5H), 1.98 (t, J=14.03Hz, 2H), 2.56 (t, J=11.00 Hz, 1H), 3.77 (t, J=7.00 Hz, 2H), 4.01 (t,J=4.50 Hz, 2H), 4.38 (t, J=4.50 Hz, 2H), 7.10 (t, J=7.50 Hz, 1H),7.19-7.36 (m, 6H), 7.39-7.44 (m, 4H), 7.53 (t, J=7.88 Hz, 1H), 9.83 (s,1H); MS (ESI) [M+1]⁺ 457.

Example D-6:2-((1r,4r)-4-(4-(4-(2-aminophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid—step d6

A solution of2-((1r,4r)-4-(4-(4-(2-nitrophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid C-27 (40.0 mg, 0.08 mmol) in ethyl acetate (10.0 mL) and methanol(5.0 mL) was stirred at room temperature for 3 h in the presence ofplatinum dioxide (4.0 mg, 0.02 mmol) under an atmosphere of hydrogen.The reaction was filtered over a pad of celite and washed with ethylacetate (5 mL). The filtrate was concentrated to dryness under reducedpressure, and the residue was purified by flash column chromatography onC₁₈ reverse phase (water:acetonitrile gradient) to give2-((1r,4r)-4-(4-(4-(2-aminophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid D-6 (30.0 mg; Yield=80%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.13 (q,J=11.50 Hz, 2H), 1.50 (q, J=11.50 Hz, 2H), 1.71-1.83 (m, 5H), 2.14 (d,J=6.00 Hz, 2H), 2.53 (m, 1H), 3.88 (t, J=4.50 Hz, 2H), 4.33 (t, J=4.50Hz, 2H), 7.18-7.23 (m, 2H), 7.30 (d, J=11.50 Hz, 2H), 7.55 (d, J=11.50Hz, 2H), 7.66-7.70 (m, 3H), 7.75 (d, J=7.50 Hz, 1H), 7.99 (d, J=8.50 Hz,1H), 9.93 (s, 1H), 12.05 (s, 1H); MS (ESI) [M+1]⁺ 486.

Example D-7:2-(7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamido)benzoicacid—step d7

Lithium hydroxide monohydrate (8.4 mg, 0.2 mmol) was added at roomtemperature to a solution of2-((1r,4r)-4-(4-(4-(2-(methoxycarbonyl)phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid C-29 (30.0 mg, 0.06 mmol) in tetrahydrofuran (5.0 mL) and water(1.0 mL). The reaction was stirred at room temperature overnight,quenched with a 1 N aqueous solution of hydrogen chloride (2.0 mL) andthen concentrated to dryness under reduced pressure. The crude residuewas purified by flash column chromatography on C₁₈ reverse phase(water:acetonitrile gradient) to give2-(7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carboxamido)benzoic acid D-7 (20.0 mg; Yield=70%). MS (ESI) [M+1]⁺ 515.

Example D-8: ethyl3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoate—stepd8

N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (244.0 mg, 0.645 mmol) was added at room temperatureto a solution of2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid C-113 (149.5 g, 0.303 mmol), ethyl 3-aminopropanoate (49.5 mg,0.322 mmol) and N-ethyl-N,N-diisopropylamine (165.0 μL, 1.0 mmol) inmethylene chloride (1.0 mL). The reaction mixture was stirred overnightat room temperature and then diluted with methylene chloride. Thesolution was washed with a 1 N aqueous solution of hydrogen chloride andthen brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness under reduced pressure. The crude oil waspurified by flash column chromatography on silica gel (1:1 hexanes:ethylacetate) to give ethyl3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoateD-8 as a white solid (166.0 mg; Yield=93%). ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 0.94 (d, J=6.75 Hz, 3H), 1.20 (br q, J=11.98 Hz,2H), 1.31-1.44 (m, 5H), 1.33 (t, J=7.00 Hz, 3H), 1.43 (d, J=6.00 Hz,3H), 1.55-1.63 (m, 4H), 1.97 (br t, J=13.75 Hz, 5H), 2.15 (d, J=6.62 Hz,2H), 2.55 (tt, J=10.75, 2.92 Hz, 1H), 2.61 (t, J=5.99 Hz, 2H), 3.12 (dd,J=13.40, 8.35 Hz, 1H), 3.29 (dt, J=19.00, 6.50 Hz 1H), 3.40 (dt,J=19.00, 6.50 Hz 1H), 3.59 (q, J=5.99 Hz, 2H), 4.22 (q, J=7.04 Hz, 2H),4.29-4.35 (m, 1H), 4.45 (dd, J=13.56, 2.52 Hz, 1H), 5.46 (t, J=5.52 Hz,1H), 6.13 (t, J=5.52 Hz, 1H), 7.17 (dd, J=8.35, 2.05 Hz, 1H), 7.21 (d,J=2.21 Hz, 1H), 7.29-7.35 (m, 2H), 7.34 (d, J=8.50 Hz, 1H), 7.54 (d,J=8.20 Hz, 1H); MS (ESI) [M+1]⁺ 592.

Example D-9:3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoicacid—step b14

Example D-9 was prepared by the procedure described for step b14, usingethyl3-(2-((1r,4r)-4-(4-(4-(hexylcarbamoyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)acetamido)propanoateD-8 as starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88 (t,J=6.75 Hz, 3H), 1.08 (br q, J=11.83 Hz, 2H), 1.24-1.33 (m, 9H),1.41-1.51 (m, 4H), 1.67-1.70 (m, 1H), 1.79 (t, J=14.50 Hz, 4H), 1.99 (d,J=6.62 Hz, 2H), 2.38 (t, J=6.94 Hz, 2H), 2.43-2.52 (m, 1H), 3.07-3.14(m, 2H), 3.21 (dd, J=13.25, 7.75 Hz, 1H), 3.27 (dd, J=12.50, 6.50 Hz,1H), 3.33 (br s, 2H), 3.97 (dd, J=13.25, 2.25 Hz, 1H), 4.21-4.26 (m,1H), 6.95 (t, J=5.36 Hz, 1H), 7.10 (d, J=2.00 Hz, 1H), 7.13 (dd, J=8.50,2.50 Hz, 1H), 7.27 (d, J=8.20 Hz, 2H), 7.53 (d, J=8.20 Hz, 2H), 7.60 (d,J=8.51 Hz, 1H), 7.90 (t, J=5.52 Hz, 1H), 12.20 (br s, 1H); MS (ESI)[M+1]⁺ 564.

Example D-10:2-((1r,4r)-4-(4-(4-hydroxy-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid—step d9

Sodium borohydride (7.4 mg, 0.20 mmol) was added at room temperature toa solution of2-((1r,4r)-4-(4-(4-oxo-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid C-152 (96.4 mg, 0.20 mmol) in anhydrous methanol (5.0 mL) under anatmosphere of argon. The reaction mixture was stirred overnight, thenconcentrated to dryness under reduced pressure. The crude residue waspurified by flash column chromatography on C₁₈ reverse phase(water:acetonitrile gradient with 0.05% formic acid) to give2-((1r,4r)-4-(4-(4-hydroxy-1-(phenylcarbamoyl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)cyclohexyl)aceticacid D-10 (63.0 mg, Yield=65%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q,J=11.6 Hz, 2H), 1.51 (q, J=11.6 Hz, 2H), 1.70-1.92 (m, 3H), 1.92-1.99(m, 2H), 2.15 (d, J=6.5 Hz, 2H), 2.50-2.60 (m, 1H), 2.90 (t, J=6.0 Hz,2H), 3.74 (t, J=6.0 Hz, 2H), 4.50 (m, 1H), 7.10 (t, J=6.0 Hz, 1H),7.25-7.35 (m, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.58-7.60 (m, 3H), 7.70-7.82(m, 2H), 7.90 (d, J=2.5 Hz, 2H), 9.50 (s, 1H), 12.10 (br s, 1H); MS(ESI) [M+1]⁺ 485.

Example:2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)aceticacid

A 4 N solution of hydrogen chloride in dioxane (3.0 mL) was added atroom temperature to a solution of2-((1r,4r)-4-(4-(4-(tert-butoxycarbonyl)-1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)aceticacid C-153 (58.3 mg, 0.10 mmol) in dioxane (10.0 mL). After 12 h ofstirring, the reaction mixture was concentrated to dryness under reducedpressure. The crude residue was purified by flash column chromatographyon C₁₈ reverse phase (water:acetonitrile gradient with 0.05% formicacid) to give2-((1r,4r)-4-(4-(1-(phenylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-yl)phenyl)cyclohexyl)aceticacid D-11 (43.5 mg, Yield=90%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q,J=12.0 Hz, 2H), 1.52 (q, J=11.58 Hz, 2H), 1.66-1.94 (m, 5H), 2.17 (d,J=7.0 Hz, 2H), 2.54 (m, 1H), 3.44-3.57 (m, 4H), 4.40 (s, 2H), 6.99 (t,J=6.5 Hz, 2H), 7.24 (t, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.41-7.44(m, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.71-7.77 (m, 1H), 7.95 (s, 1H), 9.10(s, 1H), 12.07 (br s, 1H); MS (ESI) [M+1]⁺ 484.

Example D-12:7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-2-methyl-N-phenylquinoline-4-carboxamide—stepd11

N-Ethyl-N,N-diisopropylethylamine (50.0 μL, 0.30 mmol) was added at roomtemperature to a solution of2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)-quinolin-7-yl)phenyl)cyclohexyl)aceticacid C-134 (47.8 mg, 0.1 mmol), (1H-tetrazol-5-yl)methanaminehydrobromide (27.7 mg, 0.15 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(64.0 mg, 0.12 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) underan atmosphere of nitrogen. The reaction mixture was stirred overnight,then partitioned between methylene chloride (30 mL) and an aqueoussolution of pH 7 phosphate buffer (30 mL). The aqueous layer wasextracted with methylene chloride (3×30 mL). The combined organicextracts were successively washed with water (30 mL), brine (30 mL),then dried over anhydrous magnesium sulfate and concentrated to drynessunder reduced pressure. The crude residue was purified by flash columnchromatography on silica gel (hexanes:ethyl acetate gradient) to give7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-2-methyl-N-phenylquinoline-4-carboxamideD-12 (32.2 mg, Yield=60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q,J=11.0 Hz, 2H), 1.61 (q, J=11.0 Hz, 2H), 1.59-1.85 (m, 5H), 2.11 (d,J=6.5 Hz, 2H), 2.54 (m, 1H), 2.75 (s, 3H), 4.56 (d, J=5.5 Hz, 2H),7.12-7.23 (m, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.63 (s, 1H), 7.69 (s, 1H),7.81 (q, J=9.0 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H),8.15 (d, J=8.5 Hz, 1H), 8.25 (t, J=8.5 Hz, 1H), 8.47 (s, 1H), 8.62 (t,J=5.5 Hz, 1H), 10.80 (s, 1H), 10.85 (s, 1H); MS (ESI) [M+1]⁺ 560.

Example D-13:7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-2-methyl-4-(phenylcarbamoyl)quinoline1-oxide—step d12

m-Chloroperoxybenzoic acid (30.0 mg, 0.20 mmol) was added to a solutionof2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid C-134 (47.8 mg, 0.1 mmol) in anhydrous methylene chloride (9.0 mL).The reaction was stirred at room temperature overnight, thenconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography on C₁₈ reverse phase (water:acetonitrilegradient with 0.05% formic acid) to give7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-2-methyl-4-(phenylcarbamoyl)quinoline1-oxide D-13 (17.3 mg; Yield=35%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16(q, J=11.6 Hz, 2H), 1.52 (q, J=11.6 Hz, 2H), 1.74-1.87 (m, 5H), 2.17 (d,J=7.0 Hz, 2H), 2.47-2.51 (m, 1H), 2.89 (s, 3H), 7.09-7.18 (m, 1H),7.39-7.43 (m, 2H), 7.53-7.63 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.79-7.81(m, 1H), 7.89-7.94 (m, 2H), 7.98 (d, J=8.5 Hz, 1H), 8.11 (d, J=9.0 Hz,1H), 8.39 (d, J=9.0 Hz, 1H), 8.86 (s, 1H), 10.74 (s, 1H); MS (ESI)[M+1]⁺ 495.

Example D-14:2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamothioyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid—step d13

2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide(80.0 mg, 0.20 mmol) was added dropwise to a solution of2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid C-134 (47.8 mg, 0.10 mmol) in toluene (10.0 mL). The reaction wasrefluxed overnight and then concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography on C₁₈reverse phase (water:acetonitrile gradient with 0.05% formic acid) togive2-((1r,4r)-4-(4-(2-methyl-4-(phenylcarbamothioyl)quinolin-7-yl)phenyl)cyclohexyl)aceticacid D-14 (44.4 mg; Yield=45%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (q,J=11.5 Hz, 2H), 1.53 (q, J=11.5 Hz, 2H), 1.73-1.87 (m, 5H), 2.17 (d,J=6.5 Hz, 2H), 2.54 (m, 1H), 2.72 (s, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.40(d, J=8.0 Hz, 2H), 7.43 (s, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.63 (s, 1H),7.78 (d, J=7.5 Hz, 2H), 7.93 (d, J=9.0 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H),8.06 (d, J=8.5 Hz, 1H), 8.22 (s, 1H), 12.05 (s, 1H), 12.40 (br s, 1H);MS (ESI) [M+1]⁺ 495.

Section E Additional Example Compounds Preparation of Examples E-1 toE-10

The following examples were prepared using the general proceduresoutlined in section D and section B and using selected examples ofsection C as starting material.

Example E-1:5-(4-((1r,4r)-4-(2-amino-2-oxoethyl)cyclohexyl)phenyl)-N-phenylindoline-1-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=11.65 Hz, 2H), 1.50 (q,J=11.65 Hz, 2H), 1.75 (br s, 1H), 1.78-1.90 (m, 4H), 2.15 (d, J=6.62 Hz,2H), 2.53-2.55 (m, 1H), 3.22 (t, J=8.51 Hz, 2H), 4.18 (t, J=8.51 Hz,2H), 7.23-7.30 (m, 1H) 7.31-7.45 (m, 5H) 7.46-7.58 (m, 4H), 7.63-7.81(m, 1H), 7.87-7.96 (m, 1H), 8.55 (s, 2H); MS (ESI) [M+1]⁺ 454.

Example E-2:5-(4-((1r,4r)-4-(2-(2-cyanoethylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-phenylindoline-1-carboxamide

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.22 (q, J=11.35 Hz, 2H), 1.50 (q,J=11.65 Hz, 2H), 1.75 (br s, 1H), 1.78-1.98 (m, 4H), 2.18 (d, J=6.50 Hz,2H), 2.53-2.55 (m, 1H), 2.69 (t, J=5.51 Hz, 2H), 3.32 (t, J=8.51 Hz,2H), 3.57 (q, J=6.00 Hz, 2H), 4.17 (t, J=8.51 Hz, 2H), 7.12 (t, J=7.50Hz, 1H), 7.27-7.30 (m, 5H), 7.36 (t, J=7.50 Hz, 2H), 7.43-7.52 (s, 4H),7.95 (d, J=8.00 Hz, 1H), 8.02 (s, 1H); MS (ESI) [M+1]⁺ 507.

Example E-3:2-((1r,4r)-4-(4-(4-(4-Aminophenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)cyclohexyl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.12 (q, J=11.50 Hz, 2H), 1.48 (q,J=11.50 Hz, 2H), 1.70-1.84 (m, 5H), 2.15 (d, J=6.50 Hz, 2H), 2.53 (m,1H), 3.58 (br s, 1H), 3.86 (t, J=4.50 Hz, 2H), 4.29 (t, J=4.50 Hz, 2H),7.14-7.17 (m, 5H), 7.29 (d, J=8.00 Hz, 2H), 7.48-7.58 (m, 4H), 9.29 (s,1H), 12.05 (s, 1H); MS (ESI) [M+1]⁺ 486.

Example E-4:7-(4-((1r,4r)-4-(2-(hydroxyamino)-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (q, J=11.50 Hz, 2H), 1.47 (q,J=11.50 Hz, 2H), 1.70-1.83 (m, 5H), 1.88 (d, J=6.50 Hz, 2H), 2.50 (m,1H), 3.58 (br s, 1H), 3.89 (t, J=4.50 Hz, 2H), 4.30 (t, J=4.50 Hz, 2H),7.16-7.18 (m, 4H), 7.29 (d, J=8.20 Hz, 2H), 7.46-7.62 (m, 4H), 7.66 (t,J=7.41 Hz, 2H), 8.71 (br s, 1H), 8.83 (br s, 1H), 10.39 (s, 1H); MS(ESI) [M+1]⁺ 486.

Example E-5:2-methyl-7-(4-((1r,4r)-4-(2-oxo-2-(phenylamino)ethyl)cyclohexyl)phenyl)-N-phenylquinoline-4-carboxamide

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.25-1.29 (m, 2H), 1.59-1.67 (m,5H), 1.99-2.05 (m, 3H), 2.33 (d, J=6.5 Hz, 2H), 2.84 (s, 3H), 7.14-7.28(m, 3H), 7.37 (d, J=8.0 Hz, 2H), 7.44-7.49 (m, 3H), 7.56 (d, J=8.5 Hz,2H), 7.73 (d, J=8.0 Hz, 2H), 7.80 (s, 2H), 7.86 (d, J=6.0 Hz, 2H),8.29-8.33 (m, 2H); MS (ESI) [M+1]⁺ 554.

Example E-6:7-(4-((1r,4r)-4-(2-(methylsulfonamido)-2-oxoethyl)cyclohexyl)phenyl)-N-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15-1.26 (m, 2H), 1.49 (q, J=11.5 Hz,2H), 1.76 (s, 3H), 1.76-1.88 (m, 4H), 1.73-1.87 (m, 1H), 2.25 (d, J=7.0Hz, 2H), 2.50-2.55 (m, 1H), 3.87 (t, J=4.0 Hz, 2H), 4.29 (t, J=4.0 Hz,2H), 6.55 (s, 3H), 6.99-7.05 (m, 3H), 7.15 (s, 1H), 7.29 (t, J=7.5 Hz,3H), 7.49-7.62 (m, 1H), 7.95 (s, 1H), 9.16 (s, 1H), 9.89 (br s, 1H); MS(ESI) [M+1]⁺ 540.

Example E-7:7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylquinoline-4-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.14 (q, J=12.5 Hz, 2H), 1.49 (q, J=12.5Hz, 2H), 1.72-1.87 (m, 3H), 2.11 (d, J=6.5 Hz, 2H), 2.51 (m, 1H), 2.77(s, 3H), 3.00-3.03 (m, 2H), 4.55 (d, J=5.5 Hz, 2H), 7.40 (d, J=8.00 Hz,1H), 7.60 (s, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.73-7.83 (m, 4H), 7.97 (d,J=8.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.26 (s, 1H), 8.59 (t, J=5.5 Hz,1H), 10.66 (s, 1H); MS (ESI) [M+1]⁺ 646.

Example E-8:7-(4-((1r,4r)-4-(2-(1H-tetrazol-5-ylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylquinoline-4-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.23 (q, J=12.5 Hz, 2H), 1.55 (q, J=12.5Hz, 2H), 1.87 (d, J=7.5 Hz, 5H), 2.36-2.78 (m, 3H), 2.78 (s, 3H), 7.12(d, J=8.0 Hz, 2H), 7.63 (s, 1H), 7.73 (t, J=8.5 Hz, 1H), 7.78-7.82 (m,4H), 8.00 (d, J=9.0 Hz, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.27 (s, 1H), 10.61(s, 2H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 632.

Example E-9:7-(4-((1r,4r)-4-(2-((1H-tetrazol-5-yl)methylamino)-2-oxoethyl)cyclohexyl)phenyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15 (q, J=11.6 Hz, 2H), 1.53 (q, J=11.6Hz, 2H), 1.73-1.80 (m, 5H), 2.19 (d, J=7.5 Hz, 2H), 2.54 (m, 1H), 3.05(m, 2H), 3.87 (t, J=4.0 Hz, 2H), 4.30 (t, J=4.0 Hz, 2H), 7.12-7.18 (m,1H), 7.36-7.54 (m, 2H), 7.59-7.70 (m, 2H), 7.74-7.90 (m, 2H), 8.13-8.39(m, 3H), 10.61 (s, 2H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺ 638.

Example E-10:7-(4-((1r,4r)-4-(carboxymethyl)cyclohexyl)phenyl)-4-(4-fluoro-2-(trifluoromethyl)phenylcarbamoyl)-2-methylquinoline1-oxide

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (q, J=11.5 Hz, 2H), 1.52 (q, J=11.5Hz, 2H), 1.83-1.87 (m, 4H), 2.17 (d, J=7.0 Hz, 2H), 2.37-2.67 (m, 2H),2.89 (s, 3H), 6.99 (s, 1H), 7.08 (s, 1H), 7.19 (m, 1H), 7.45 (t, J=8.0Hz, 2H), 7.71-7.91 (m, 2H), 8.11 (m, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.67(s, 1H), 8.86 (s, 1H), 10.61 (s, 1H), 12.05 (br s, 1H); MS (ESI) [M+1]⁺581.

Biological Assay

The assay used to determine the DGAT inhibitory activity of theinventive compounds is described below:

The in vitro assay to identify DGAT1 inhibitors uses human DGAT1 enzymeexpressed in Sf9 insect cells prepared as microsomes. The reaction wasinitiated by the addition of the combined substrates1,2-dioleoyl-sn-glycerol and [¹⁴C]-palmitoyl-CoA and incubated with testcompounds and microsomal membranes for 2 hours at room temperature. Theassay was stopped by adding 0.5 mg wheat germ agglutinin beads in assaybuffer with 1% Brij-35 and 1%3-cholamidopropyldimethyl-ammonio-1-propane sulfonate. Plates weresealed with TopSeal and incubated for 18 hours to allow the radioactivetriglyceride product to come into proximity with the bead. Plates wereread on a TopCount instrument.

Percent inhibition was calculated as the percent of (test compoundinhibition minus non-specific binding) relative to (total binding minusnon-specific binding). IC₅₀ values were determined by curve fitting thedata to a Sigmoidal dose-response in GraphPad Prism utilizing thefollowing equation:

Y=A+(B−A)/(1+10̂((LogIC₅₀ −X))),

where A and B are the bottom and top of the curve (highest and lowestinhibition), respectively, and X is the logarithm of concentration.

Biological Data Compound human DGAT1 Number Structure IC50 (nM) C-6

20 B-48

83 C-78 enantiomer A

79 C-125

72 B-18 enantiomer A

43 C-82 enantiomer B

88 C-81 enantiomer A

58 C-129

94 C-134

28 C-113

82 C-139

61 C-116

71 C-141

15 C-150

83 C-142

12

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

1-12. (canceled)
 13. A compound, or pharmaceutically acceptable salt ofsaid compound, the compound being represented by the Formula IA:

or a stereoisomer or tautomer of said compound, wherein the bond denotedby

represents a single bond or a double bond; W is selected from the groupconsisting of N, or N(R⁴); X is selected from the group consisting ofC(R⁴), or C(R⁴R⁴); Y is selected from the group consisting of C(R⁴), orC(R⁴R⁴); R⁴ is present depending on the allowed valency and R⁴ isselected from H, alkyl, R¹, —OH, (═O), or hydroxyalkyl; W, X or Y issubstituted with R¹ depending on the allowed valency; R¹ is selectedfrom the group consisting of -alkyl, -aryl, arylalkyl-, heteroaryl-,(alkylamino)carbonyl-, (cycloalkylamino)carbonyl-,(heterocycloalkylamino)carbonyl-, (arylamino)carbonyl-,(heteroarylamino)carbonyl-, wherein each of these R¹ groups isunsubstituted or optionally independently substituted with 1-4substituents independently selected from halogen, amino, alkylamino,hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester,methylenedioxy, CN, cyanoalkyl-, nitro and CF₃; A is C(R⁵); B is C(R⁵);C is C(R⁵); D is C(R⁵); R⁵ is selected from H, alkyl, cycloalkyl, amino,alkylamino, hydroxy, alkoxy, halogen or R²; A, B, C or D is optionallysubstituted, depending on the allowed vacancy, with cycloalkyl,heterocyclyl, heteroaryl and aryl, wherein each of these groups isunsubstituted or optionally independently substituted with 1-4substituents independently selected from halogen, amino, alkylamino,hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF₃; R² is aryl, wherein thearyl is unsubstituted or optionally independently substituted with 1-4substituents independently selected from halogen, amino, alkylamino,hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF₃; Z is a bond; R⁶ isselected from H or alkyl; R³ is cycloalkyl, wherein the cycloalkyl isunsubstituted or optionally independently substituted with 1-4substituents independently selected from halogen, amino, alkylamino,hydroxy, alkoxy, alkyl, cycloalkyl, —CN, —CF₃, —C(O)NH(R⁶), —CON(R⁶)₂,—COOH, —C(O)—Oalkyl, -alkylCOOH, -alkyl-C(O)O-alkyl, -alkyl-C(O)NH₂,-alkyl-C(O)—NH—(CH₂)₁₋₃—CN, -alkyl-C(O)—NH—(CH₂)₁₋₃-(heteroaryl), —COOHbioisostere or -alkylCOOH bioisostere.
 14. A pharmaceutical compositioncomprising at least one compound of claim 13 and at least onepharmaceutically acceptable carrier.
 15. A method of inhibiting DGAT1 ina patient in need thereof comprising administering therapeuticallyeffective amounts of at least one compound of claim 13 to said patient.16. A method of treating obesity, diabetes or metabolic syndrome in apatient in need thereof comprising administering therapeuticallyeffective amounts of at least one compound of claim 13 to said patient.17. A compound of claim 13, selected from any of the followingcompounds:

or a pharmaceutically acceptable salt thereof.
 18. A compound, orpharmaceutically acceptable salt of said compound, the compound beingrepresented by the Formula IB:

or a stereoisomer or tautomer of said compound, wherein the bond denotedby

represents a single bond or a double bond; E is selected from the groupconsisting of N, N(R⁴) or O; F is selected from the group consisting ofC(R⁴), or C(R⁴R⁴); G is selected from the group consisting of C(R⁴), orC(R⁴R⁴); H is selected from the group consisting of C(R⁴), C(R⁴R⁴), N orN(R⁴); R⁴ is present depending on the allowed vacancy and is selectedfrom H, alkyl, R¹, —OH, (═O), or hydroxyalkyl; E, F, G or H issubstituted with R¹ depending on the allowed valency; R¹ is selectedfrom the group consisting of alkyl-, aryl-, arylalkyl-, heteroaryl-,(alkylamino)carbonyl-, (cycloalkylamino)carbonyl-,(heterocycloalkylamino)carbonyl-, (arylamino)carbonyl-, wherein each ofthese R¹ groups is unsubstituted or optionally independently substitutedwith 1-4 substituents independently selected from halogen, amino,alkylamino, hydroxy, alkoxy, alkyl, cycloalkyl, carboxy, carboxyester,methylenedioxy, CN, cyanoalkyl-, nitro and CF₃; A is CR⁵; B is CR⁵; C isCR⁵; D is CR⁵; R⁵ is selected from H, alkyl, cycloalkyl, amino,alkylamino, hydroxy, alkoxy, halogen or R²; A, B, C or D is optionallysubstituted, depending on the allowed valency, with cycloalkyl,heterocyclyl, heteroaryl and aryl, wherein each of these groups isunsubstituted or optionally independently substituted with 1-4substituents independently selected from halogen, amino, alkylamino,hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF₃; R² is aryl, wherein thearyl is unsubstituted or optionally independently substituted with 1-4substituents independently selected from halogen, amino, alkylamino,hydroxy, alkoxy, alkyl, cycloalkyl, CN and CF₃; Z is a bond; and R³ isselected from the group consisting of cycloalkyl, heterocyclyl, aryl andheteroaryl, wherein each of these R³ groups is unsubstituted oroptionally independently substituted with 1-4 substituents independentlyselected from halogen, amino, alkylamino, hydroxy, alkoxy, alkyl,cycloalkyl, —CN, —CF₃, —C(O)NH(R⁶), —CON(R⁶)₂, —COOH, —C(O)—Oalkyl,-alkylCOOH, -alkyl-C(O)O-alkyl, -alkyl-C(O)NH₂,-alkyl-C(O)—NH—(CH₂)₁₋₃—CN, -alkyl-C(O)—NH—(CH₂)₁₋₃-(heteroaryl), —COOHbioisostere or -alkylCOOH bioisostere.
 19. A pharmaceutical compositioncomprising at least one compound of claim 18 and at least onepharmaceutically acceptable carrier.
 20. A method of inhibiting DGAT1 ina patient in need thereof comprising administering therapeuticallyeffective amounts of at least one compound of claim 18 to said patient.21. A method of treating obesity, diabetes or metabolic syndrome in apatient in need thereof comprising administering therapeuticallyeffective amounts of at least one compound of claim 18 to said patient.22. A compound selected from the compounds of the formulae:

or a pharmaceutically acceptable salt thereof.